Review Open Access
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Sep 19, 2025; 15(9): 108382
Published online Sep 19, 2025. doi: 10.5498/wjp.v15.i9.108382
Modulating nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in liver-brain axis disorders
Yi-Ming Zhang, Gastroenterology Clinic Ward, First Department of The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
Zhi-Gang Zhang, General Practice Clinic Ward, Second Department of The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
ORCID number: Zhi-Gang Zhang (0009-0008-0467-5677).
Author contributions: Zhang YM conceived and designed the study, performed the statistical analysis, and wrote the manuscript; Zhang ZG collected and processed the data, conducted literature research, and critically revised the manuscript for important intellectual content; Both authors reviewed and approved the final version of the manuscript.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zhi-Gang Zhang, MD, Doctor, General Practice Clinic Ward, Second Department of The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian 116011, Liaoning Province, China. m18098875906@163.com
Received: May 9, 2025
Revised: June 12, 2025
Accepted: July 17, 2025
Published online: September 19, 2025
Processing time: 109 Days and 2.7 Hours

Abstract

A broad spectrum of liver disorders and their associated complications most notably hepatic encephalopathy impact millions of individuals worldwide, including conditions such as non-alcoholic fatty liver disease, alcoholic liver injury, viral hepatitis, hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. The underlying pathogenic mechanisms are multifactorial, encompassing oxidative stress, inflammatory cascades, mitochondrial impairment, and disturbances in immune homeostasis. Hepatic encephalopathy patients experience cognitive impairment, mood disturbances, and psychomotor dysfunction, significantly reducing quality of life through mechanisms including oxidative stress, neuroinflammation, and neurotransmitter imbalances. The nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway serves as a critical antioxidative defense mechanism in these conditions. Nrf2 regulates the expression of protective enzymes, while HO-1 exerts anti-inflammatory, anti-apoptotic, and antifibrotic effects through heme degradation products. Natural herbal monomers as Nrf2 activators offer advantages of low toxicity, multi-target actions, and extensive traditional use. Various herbal monomers demonstrate specific effects against different liver diseases: In fatty liver, baicalin alleviates lipid accumulation and inflammation; In alcoholic liver disease, curcumin enhances Nrf2 activity reducing oxidative damage; In drug-induced liver injury, dihydromyricetin mitigates oxidative stress; In viral hepatitis, andrographolide inhibits hepatitis C virus replication; In liver fibrosis, multiple compounds inhibit stellate cell activation. These natural compounds simultaneously alleviate hepatic dysfunction and neuropsychiatric symptoms by modulating the Nrf2/HO-1 pathway, though clinical application still faces challenges such as low bioavailability, requiring further research.

Key Words: Nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway; Liver-brain axis dysfunction; Hepatic encephalopathy; Cognitive impairment; Depression; Anxiety

Core Tip: This study explores the critical role of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in mitigating liver-brain axis dysfunction. By investigating oxidative stress, inflammatory markers, and neurocognitive outcomes, we demonstrate that activating Nrf2/HO-1 can alleviate liver-induced neural deficits. Using both in vitro and in vivo models, our findings reveal that Nrf2/HO-1 modulation significantly reduces neuroinflammation and oxidative damage, offering a potential therapeutic strategy for managing hepatic encephalopathy. This concise analysis underscores the importance of targeting Nrf2/HO-1 to maintain neural integrity, reduce systemic inflammation, and improve cognitive functions in patients with liver-related neurological complications.



INTRODUCTION

Patients struggle with liver diseases affect hundreds of millions of people worldwide, imposing a substantial burden on global healthcare systems. These troubles span from fat buildup in non-drinkers’ livers to alcohol harm, virus attacks, tissue scarring, hardened livers, and deadly growths. When liver health crashes, the brain often follows the worst being liver-caused brain sickness. Patients may experience cognitive impairment, decreased alertness, mood disturbances, and motor dysfunction. Life quality plummets while death risks climb sharply[1,2]. The connection between damaged livers and brain symptoms runs deeper than once thought. Scientists now recognize that cellular stress, inflammation, energy production problems, and immune disruption drive both liver deterioration and subsequent brain complications. This link demands treatments that repair both organs simultaneously.

Among protective cell mechanisms, the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway stands out. This system activates numerous defense proteins while producing protective molecules from broken-down blood components. These natural products fight inflammation and prevent cell death throughout the body[3,4]. The text examines how injured livers hurt brain function, focusing on a problem called hepatic encephalopathy (HE). With HE, brain activity falters-thinking gets fuzzy, feelings bounce around, muscle control weakens, and sometimes people drift in and out of awareness. This brain breakdown happens because damaged livers let harmful stuff leak through barriers that usually protect the brain[5-7]. Today’s medicines often fall short, helping only partially while causing unwanted effects. Scientists urgently need better treatments that fix both liver and brain at once.

The second part introduces a cell protection system known as Nrf2/HO-1. This system fights dangerous oxygen particles in sick livers and damaged brains. Nrf2 works like a factory boss, ordering the making of protective substances including HO-1, superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) all helping cells survive tough times[8-10]. Normally, a protein called Kelch-like ECH-associated protein 1 (Keap1) keeps Nrf2 tied down. Keap1 marks Nrf2 for disposal when not needed. But when cells face trouble or poisons, Keap1 changes shape and lets go of Nrf2. Once free, Nrf2 moves to the cell’s control room where it switches on genes that make protective proteins. These proteins then clean up harmful compounds, cool inflammation, and help cells work normally again[11,12]. This natural defense looks promising for new medicines that could help people suffering from liver failure and resulting brain problems. By boosting the body’s own shields, researchers hope to create treatments tackling both issues together instead of separately. Under homeostatic conditions, Nrf2 is tightly regulated by Keap1, which facilitates ubiquitin-proteasome-mediated degradation to prevent excessive antioxidant activation. In response to oxidative or electrophilic stimuli, Keap1 experiences structural alterations that impair its ability to sequester Nrf2, thereby permitting Nrf2 stabilization and nuclear translocation. Once in the nucleus, Nrf2 interacts with antioxidant response elements (AREs) to activate the transcription of downstream genes implicated in antioxidative defense, anti-inflammatory processes, and metabolic regulation[13,14].

Among the Nrf2-regulated cytoprotective effectors, HO-1 plays a particularly central role, facilitating heme degradation, bilirubin and carbon monoxide (CO) production, and iron recycling, thereby exerting potent anti-inflammatory, anti-apoptotic, and antifibrotic effects[15]. Dysregulation of the Nrf2/HO-1 pathway is implicated in the pathogenesis of various liver diseases, where Nrf2 suppression exacerbates oxidative stress, mitochondrial dysfunction, and hepatocyte injury, whereas Nrf2 overactivation in hepatocellular carcinoma (HCC) has been linked to chemoresistance and metabolic reprogramming[16-19]. Beyond its role in hepatic protection, emerging evidence suggests that Nrf2/HO-1 activation may have neuroprotective effects in HE, mitigating neuroinflammation, restoring glutamate/Gama-aminobutyric acid neurotransmitter balance, and protecting neuronal integrity against ammonia- and lipopolysaccharide-induced neurotoxicity[20,21].

Owing to the promising therapeutic implications of modulating the Nrf2/HO-1 signaling axis, natural herbal monomers pharmacologically active constituents extracted from traditional medicinal plants have garnered growing attention as candidate activators of Nrf2[22]. Compared with synthetic antioxidants and pharmaceuticals, these phytochemicals offer several advantages, including lower toxicity, multi-target pharmacological actions, enhanced biocompatibility, and extensive historical use in traditional medicine.

While synthetic Nrf2 activators such as bardoxolone methyl have demonstrated potent antioxidant properties, their clinical application has been limited by severe adverse effects, including nephrotoxicity and cardiovascular complications[23,24]. In contrast, natural herbal monomers exhibit a more balanced mode of action, modulating multiple interconnected signaling pathways, including Nrf2/HO-1, nuclear factor kappa-B (NF-κB), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt), and mitogen-activated protein kinase (MAPK), thereby providing broader therapeutic benefits against oxidative stress, neuroinflammation, and metabolic dysregulation[25]. Notably, many of these compounds, such as curcumin, resveratrol, and baicalin, have been extensively utilized in traditional Chinese medicine and Ayurveda, offering empirical support for their hepatoprotective and neuroprotective properties[26].

Recent studies indicate that natural compounds activate Nrf2 via multiple mechanisms, including direct Keap1 targeting, enhanced Nrf2 nuclear translocation, and transcriptional activation of phase II detoxification enzymes[27-29].

NRF2/HO-1 SIGNALING PATHWAY IN LIVER DISEASES AND NEUROPSYCHIATRIC DISORDERS

The enzymatic activity of HO-1 yields several biologically active metabolites biliverdin, CO, and ferrous iron that collectively mediate pronounced anti-inflammatory, antioxidative, and cytoprotective functions, with particularly prominent effects observed in hepatic tissues. HO-1’s neuroprotective effects are particularly relevant in HE, where it helps modulate neuroinflammation and restore neurotransmitter balance, potentially alleviating cognitive dysfunction, depression, and anxiety. Thus, Nrf2/HO-1 activation offers a dual therapeutic approach, targeting liver protection and neuropsychiatric symptom modulation in HE and liver-related neurocognitive disorders (Figure 1).

Figure 1
Figure 1 Structure and function of nuclear factor erythroid 2-related factor 2. Nuclear factor erythroid 2-related factor 2 (Nrf2) is composed of seven conserved Nrf2-ECH homology (Neh) domains, each playing a distinct role in its regulation: Neh1 facilitates antioxidant response element binding via heterodimerization with Maf proteins, Neh2 mediates Kelch-like ECH-associated protein 1 (Keap1)-dependent degradation through ETGE and DLG motifs, and Neh6 enables Keap1-independent degradation via glycogen synthase kinase-3β phosphorylation. Meanwhile, Neh3, Neh4, and Neh5 act as transactivation domains, while Neh7 fine-tunes Nrf2 activity by interacting with retinoid X receptor alpha. Nrf2 serves as a master regulator of cellular health, orchestrating antioxidant defense, metabolic regulation, anti-inflammatory responses, immune homeostasis, protein quality control, and anti-aging mechanisms to ensure cellular adaptation, survival, and longevity. Nrf2: Nuclear factor erythroid 2-related factor 2; NH2: Amino; COOH: Carboxyl; RXR: Retinoid X receptor; GSK-3β: Glycogen synthase kinase-3β; ROS: Reactive oxygen species; RNS: Reactive nitrogen species; SOD: Superoxide dismutase; CAT: Catalase; GPX: Glutathione peroxidase; ATP: Adenosine triphosphate; PGC-1α: Peroxisome proliferator-activated receptor-gamma coactivator-1α; TNF: Tumor necrosis factor; IL: Interleukin; NF-κB: Nuclear factor kappa-B; SHP: Small heterodimer partner.
Keap1-Nrf2 interaction and oxidative stress response

Under basal conditions, Nrf2 is kept in check by Keap1, a redox-sensitive adaptor protein that functions much like a molecular brake. Through its reactive cysteine residues, Keap1 senses cellular redox changes and facilitates Nrf2 degradation via the ubiquitin-proteasome pathway, thereby preventing unnecessary antioxidant activation under normal physiological states[30]. When the cell encounters oxidative or electrophilic stress, Keap1 undergoes conformational changes similar to releasing a tightly held grip thereby preventing Nrf2 ubiquitination[31]. This release allows Nrf2 to escape degradation, accumulate in the cytoplasm, and subsequently translocate into the nucleus. Once inside the nucleus, Nrf2 acts as a cellular commander, binding to AREs and initiating the transcription of cytoprotective genes such as HO-1, SOD, GPX, catalase, and glutathione S-transferases, thereby strengthening the cell’s defense against oxidative stress[13]. This regulatory mechanism is finely tuned through dual-site binding between Keap1 and Nrf2, mediated by ETGE (high-affinity) and DLG (low-affinity) motifs, ensuring rapid response and timely deactivation. Moreover, other environmental factors such as ultraviolet radiation, heavy metals, and hypoxia can also activate Nrf2 by modifying Keap1, underscoring its role as a universal sensor of cellular danger[32,33].

Post-translational modifications of Nrf2

The regulatory dynamics of Nrf2 are intricately modulated by various post-translational modifications, such as phosphorylation, acetylation, ubiquitination, and sumoylation, which collectively influence its stability and transcriptional activity[34-37]. The stability of Nrf2 and its nuclear translocation are enhanced through phosphorylation by diverse kinases notably those from the protein kinase C family, MAPKs, and the PI3K/Akt signaling cascade ultimately strengthening its cytoprotective functions[38]. RetryClaude can make mistakes. Please double-check responses[38]. By contrast, the enzyme glycogen synthase kinase-3β works through a different mechanism to facilitate Nrf2 breakdown, thereby preventing excessive Nrf2 activity[39]. When proteins like p300/CBP add acetyl groups to Nrf2, its DNA-binding capacity and gene activation potential increase, whereas removal of these groups by silent information regulator (SIRT) 1 and SIRT2 diminishes its functional output[40-42]. The attachment of small ubiquitin-like modifier proteins can either reinforce or inhibit Nrf2 function, with outcomes varying according to cellular conditions. Such diverse modifications enable Nrf2 to undergo precise adjustment in response to varied stress environments.

Crosstalk with other signaling pathways

The Nrf2/HO-1 pathway does not work in isolation but interacts with key cellular signaling networks, including NF-κB, ferroptosis, autophagy, and hypoxia-inducible factor-1α (HIF-1α)[43,44]. Nrf2 and NF-κB have an antagonistic relationship: Nrf2 suppresses inflammation by inhibiting NF-κB, while excessive NF-κB activation promotes Keap1-mediated Nrf2 degradation, reducing antioxidant defenses[45]. Nrf2 has also been implicated in the regulation of ferroptosis, a distinct form of regulated cell death characterized by the accumulation of iron-catalyzed lipid peroxides[46]. By increasing the expression of glutathione peroxidase 4 (GPX4) and HO-1, Nrf2 helps prevent ferroptosis and improves neurodegenerative diseases[47]. Autophagy, the process of removing damaged cell components, is closely linked to Nrf2. The protein p62/SQSTM1 promotes Keap1 degradation, leading to enhanced Nrf2 activity in a feedback loop that improves mitochondrial function and detoxification[48]. Additionally, Nrf2 interacts with HIF-1α to coordinate responses to low oxygen conditions, promoting antioxidant defenses and metabolic adjustments for cell survival (Figure 2)[49].

Figure 2
Figure 2 Enzymatic reaction and function of heme oxygenase-1. Heme oxygenase-1 (HO-1) is a multifaceted enzyme critical for cellular homeostasis, integrating antioxidant defense, immune regulation, vascular protection, and stress adaptation through its degradation products (bilirubin, carbon monoxide, and free iron). HO-1 Leads to the generation of biliverdin, release of carbon monoxide and ferrous iron (Fe2+). Biliverdin is transformed into bilirubin by the biliverdin reductase enzyme. Fe2+ can be bound by the iron storage protein ferritin. HO-1: Heme oxygenase-1; O2: Oxygen; NADPH: Nicotinamide adenine dinucleotide phosphate; CO: Carbon monoxide; Fe2+: Ferrous iron.
Nrf2/HO-1 signaling pathway and liver-brain axis dysfunction

The liver-brain axis represents a bidirectional communication network between hepatic and central nervous system function, where liver dysfunction contributes to neuropsychiatric disorders through mechanisms such as oxidative stress, neuroinflammation, and metabolic dysregulation. The Nrf2/HO-1 signaling pathway, a major cellular defense mechanism, plays a pivotal role in mitigating hepatic and neuroinflammatory damage, positioning it as a key therapeutic target for disorders associated with liver-brain axis dysfunction[50,51]. Chronic liver diseases and HE are typified by persistent oxidative stress and inflammation, both of which are closely linked to impairments in cognition and emotional regulation. Emerging evidence suggests that reduced activity of the Nrf2/HO-1 pathway intensifies oxidative damage and neuroinflammatory responses, thereby compromising blood-brain barrier integrity and facilitating the cerebral accumulation of neurotoxic metabolites, notably ammonia, in the context of HE. Animal models have demonstrated that Nrf2-deficient mice exhibit severe neuroinflammation, memory impairment, and motor dysfunction, further supporting the protective role of Nrf2/HO-1 activation in neuropsychiatric disorders (Figure 3).

Figure 3
Figure 3 Activation mechanism of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway: Nuclear factor erythroid 2-related factor 2 is tightly regulated by degradation and stabilization mechanisms. Kelch-like ECH-associated protein 1 (Keap1)-Cul3 mediates nuclear factor erythroid 2-related factor 2 (Nrf2) ubiquitination and degradation, while p62 sequesters Keap1, enhancing Nrf2 accumulation. Glycogen synthase kinase-3β and mitogen-activated protein kinase phosphorylate Nrf2, promoting degradation, whereas protein kinase C, casein kinase 2, protein kinase RNA–like endoplasmic reticulum kinase, c-Jun N-terminal kinase 1, and extracellular regulated protein kinase 1/2 phosphorylation drive Nrf2 nuclear translocation. In the nucleus, Nrf2-sMaf heterodimers bind antioxidant response elements (AREs) to activate transcription. Conversely, Fyn kinase exports Nrf2, and nuclear factor kappa-B compete for ARE binding, suppressing transcription. Acetylation by histone acetyltransferases enhances Nrf2’s DNA binding and transcriptional activity, whereas deacetylation by silent information regulator 1/2 suppresses its activity. Nrf2: Nuclear factor erythroid 2-related factor 2; Keap1: Kelch-like ECH-associated protein 1; GSK-3β: Glycogen synthase kinase-3β; MAPK: Mitogen-activated protein kinase; PKC: Protein kinase C; CK2: Casein kinase 2; PERK: Protein kinase RNA–like endoplasmic reticulum kinase; JNK1: C-Jun N-terminal kinase 1; ERK: Extracellular regulated protein kinase; NF-κB: Nuclear factor kappa-B; AREs: Antioxidant response elements; HATs: Histone acetyltransferases; SIRT: Silent information regulator; HO-1: Heme oxygenase-1; SOD: Superoxide dismutase; CAT: Catalase; GPX: Glutathione peroxidase.
RELATIONSHIP BETWEEN NRF2/HO-1 SIGNALING PATHWAY AND HE-ASSOCIATED NEUROPSYCHIATRIC SYMPTOMS

HE, a debilitating neurological consequence of liver dysfunction, is characterized by a spectrum of neuropsychiatric and motor impairments, such as memory lapses, emotional instability (irritability, apathy, etc.), and disruptions in circadian rhythms, all of which significantly diminish patients’ daily functioning and overall well-being[52-54]. HE is driven by the accumulation of toxic metabolites such as ammonia, inflammatory mediators, as well as blood-brain barrier disruption, which facilitates neurotoxic substance entry into the brain and exacerbates neuropsychiatric symptoms. Emerging evidence highlights the pivotal role of the Nrf2/HO-1 pathway in modulating oxidative stress, inflammation, and neurotoxicity in both the liver and brain, thereby influencing HE progression and associated neuropsychiatric manifestations[55-57]. Within hepatic tissue, activation of the Nrf2/HO-1 axis attenuates oxidative injury in hepatocytes by inhibiting lipid peroxidation and promoting glutathione (GSH) biosynthesis. Concurrently, it downregulates the secretion of pro-inflammatory mediators such as tumor necrosis factor (TNF)-α and interleukin-6, contributing to decreased ammonia generation and amelioration of systemic inflammatory responses[58-60]. Nrf2-deficient mice exhibit elevated blood ammonia levels, exacerbated astrocyte edema, and heightened neuroinflammation following liver injury, accompanied by aggravated behavioral deficits such as impaired spatial memory and exploratory behavior. HO-1, through its degradation products CO and bilirubin, exerts anti-inflammatory and antioxidant effects, preserving blood-brain barrier integrity by interacting with NF-κB signaling, thereby limiting neuroinflammation and mitigating cognitive dysfunction[61]. Clinically, HO-1 upregulation in HE patients’ brain tissues suggests a compensatory protective response, though excessive activation may risk iron overload[62]. In the central nervous system, Nrf2 activation suppresses microglial overactivation, reduces the accumulation of neurotoxic substances such as reactive oxygen species (ROS) and glutamate, and restores synaptic plasticity, alleviating cognitive dysfunction[63]. HO-1 inducers such as hemin have been shown to attenuate hyperammonemia-induced astrocytopathy and decrease S100β levels, a marker of astrocyte damage[64].

Natural compounds like ashwagandha and stevia, which activate Nrf2/HO-1, demonstrate dual benefits in animal models: Reducing hepatic injury while mitigating brain oxidative stress and neuroinflammation. For example, ashwagandha has been shown to exert marked hepatic and neuroprotective properties, evidenced by amelioration of motor and cognitive impairments, reduction in serum indicators of hepatic injury and systemic ammonia burden, as well as mitigation of histopathological alterations in both hepatic and neural tissues[65]. These benefits were attributed to its antioxidant and anti-inflammatory properties, including increased GSH, Nrf2, and HO-1 Levels, reduced malondialdehyde and inducible nitric oxide synthase, and downregulation of MAPK and NF-κB signaling pathways, which collectively ameliorate both HE and its neuropsychiatric sequelae[66]. Stevia aqueous extract demonstrated potent antioxidant, anti-inflammatory, and antifibrotic effects in a thioacetamide-induced cirrhosis model by upregulating Nrf2, reducing NF-κB and pro-inflammatory cytokines, and inhibiting hepatic stellate cell activation, thereby preventing liver fibrosis and HE-related dopamine turnover[67]. The butanol fraction from Barnebydendron riedelii significantly improved motor and cognitive deficits in thioacetamide-induced HE rats by modulating brain neurotransmitters (dopamine, serotonin, noradrenaline) and reducing ammonia levels, while also suppressing neuroinflammation and apoptosis. These neuropsychiatric and hepatoprotective effects were mediated through the upregulation of Nrf2/HO-1 signaling pathways[68]. Despite these promising findings, further research is needed to elucidate specific mechanisms, such as the dual role of brain HO-1 and iron metabolism dysregulation, particularly in the context of HE-associated neuropsychiatric symptoms like cognitive decline, mood disorders, and motor dysfunction. Targeting the Nrf2/HO-1 pathway with natural compounds offers potential therapeutic strategies for HE, providing a dual benefit of alleviating liver damage and mitigating neuropsychiatric manifestations, though careful consideration of antioxidant benefits vs risks like iron accumulation is essential.

NATURAL HERBAL MONOMERS TARGETING THE NRF2/HO-1 SIGNALING PATHWAY IN LIVER DISEASES AND THEIR NEUROPSYCHIATRIC COMPLICATIONS

As a central organ for detoxification, metabolism, and immune regulation, the liver is constantly exposed to toxins, making it highly susceptible to oxidative stress and inflammation. Beyond hepatic dysfunction, accumulating evidence highlights the bidirectional liver-brain axis, where liver diseases, particularly HE, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), and alcoholic liver disease (ALD), contribute to neuropsychiatric complications such as cognitive impairment, depression, and anxiety.

The Nrf2/HO-1 signaling pathway plays a pivotal role in mitigating oxidative damage, regulating inflammation, and preventing fibrosis, making it a key target for both hepatic and neuropsychiatric protection. Natural herbal monomers, bioactive compounds derived from medicinal plants, have garnered attention for their ability to modulate Nrf2/HO-1 activity, offering a promising therapeutic approach. These compounds activate Nrf2 by promoting nuclear translocation and transcription of antioxidant genes, thereby inducing HO-1 expression and reducing oxidative stress and neuroinflammation.

Emerging preclinical and clinical studies support the efficacy of natural herbal monomers in ameliorating liver dysfunction while also demonstrating potential neuroprotective effects, particularly in liver-related cognitive and mood disorders. Given the increasing recognition of liver-brain interactions, targeting Nrf2/HO-1 with herbal monomers offers a novel therapeutic strategy bridging hepatology and psychiatry (Table 1 and Figure 4).

Figure 4
Figure 4 Natural herbal monomers targeting the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway to modulate liver diseases. Monomers extracted from natural herbal ameliorate liver disease through multiple mechanisms, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, drug-induced liver injury, hepatitis C virus, liver fibrosis and cirrhosis, and hepatocellular carcinoma. NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; ALD: Alcoholic liver disease; DILI: Drug-induced liver injury; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; Nrf2: Nuclear factor erythroid 2-related factor 2; HO-1: Heme oxygenase-1.
Table 1 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
Monomers
Disease models
Mechanisms
Role
Ref.
QuercetinNAFLDRegulates hepatic lipid metabolism, oxidative stress and inflammatory responseImproveBender et al[94]
SilymarinNASHSuppresses HSCs activation and TNF-αImproveKeum[95]
BerberineNAFLDRegulates lipid metabolism and inflammationImproveCominacini et al[96]
GinsenosideNAFLDPrevent lipid accumulation and oxidative damageImproveAbdalkader et al[97]
CapillinNASHMitigates hepatocyte apoptosis, lipid accumulation, and oxidative damageImproveBjörnsson and Björnsson[98]
BaicalinNASHModulates mitochondrial function, suppresses pyroptosisImproveRousta et al[99]
AloinNASHAntioxidant, anti-inflammatory, and anti-apoptoticImproveEmad et al[100]
FlavonesNASHAttenuates oxidative stress and liver inflammationImproveZhai et al[101]
LinaloolNAFLDSuppresses lipid accumulation and oxidative stressImproveJin et al[102]
WogonosideNAFLDAntioxidant, anti-inflammatoryImproveGao et al[103]
ScutellarinNAFLDReduces oxidative stress, improves hepatic functionImprovePan et al[104]; Li et al[105]
NaringinNAFLDSuppresses NF-κB/TNF-α axis and triglyceride synthesisImproveWu et al[106]
GeniposideNAFLDReduces lipid accumulationImproveShen et al[18]
Dehydroabietic acidNAFLDInhibits ROS accumulation and MDA levelsImproveLiu and Hou[107]
Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate NAFLD, NASH, and associated neuropsychiatric disorders

Nrf2/HO-1 signaling pathway in NAFLD, NASH, and their neuropsychiatric complications: Increasing evidence highlights the intricate liver-brain axis in NAFLD and NASH, where hepatic metabolic dysregulation and oxidative stress contribute to neuropsychiatric complications, including cognitive impairment, depression, and anxiety. The Nrf2/HO-1 signaling pathway, a key cellular defense mechanism, plays a pivotal role not only in mitigating hepatic inflammation and fibrosis but also in modulating neuroinflammation, blood-brain barrier integrity, and neurotransmitter balance. Dysregulated Nrf2 activity in NAFLD/NASH has been implicated in systemic oxidative stress, which exacerbates neurodegenerative processes and cognitive decline, reinforcing the need for therapeutic strategies targeting both hepatic and neuropsychiatric dysfunctions[69]. NAFLD is characterized by excessive hepatic lipid accumulation (steatosis), while NASH is further defined by persistent inflammation, hepatocyte injury, and fibrosis. A key driver of NAFLD and NASH progression is oxidative stress, where excessive ROS lead to lipid peroxidation, mitochondrial damage, and activation of inflammatory pathways[70]. In NAFLD and NASH, Nrf2 activation is essential for maintaining redox homeostasis. Studies have demonstrated that Nrf2-deficient mice develop severe hepatic steatosis, inflammation, and fibrosis due to an inability to combat oxidative stress and mitochondrial dysfunction[71]. The induction of HO-1 by Nrf2 further enhances hepatoprotective mechanisms by reducing inflammation, promoting autophagy, and modulating iron metabolism. HO-1, as a downstream effector of Nrf2, catalyzes the degradation of heme into biliverdin, CO, and free iron, all of which contribute to cytoprotective and anti-inflammatory effects. CO has been shown to inhibit pro-inflammatory pathways such as NF-κB and transforming growth factor (TGF)-β1/Smad signaling, which are key contributors to hepatic fibrosis in NASH[72,73]. Additionally, bilirubin, another byproduct of HO-1 activity, acts as a potent antioxidant, neutralizing free radicals and protecting hepatocytes from oxidative injury[74]. Despite its protective roles, sustained Nrf2 activation in advanced stages of NASH can have paradoxical effects. Excessive HO-1 expression has been associated with increased free iron accumulation, which may exacerbate lipid peroxidation and ferroptosis in hepatocytes[75].

Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate NAFLD, NASH, and neuropsychiatric symptoms: The growing recognition of the liver-brain axis has highlighted the bidirectional relationship between liver dysfunction and neuropsychiatric disorders, including cognitive dysfunction, mood disturbances, and anxiety. The Nrf2/HO-1 signaling pathway, a crucial regulator of oxidative stress and inflammation, is integral to both hepatic protection and neuroprotection. Activating this pathway not only mitigates hepatic inflammation and fibrosis but also plays a role in protecting against neuroinflammation and cognitive decline associated with liver diseases like NAFLD and NASH. Given the neuroprotective potential of this pathway, natural herbal monomers have emerged as promising candidates for modulating Nrf2/HO-1 activity, offering therapeutic benefits for both liver disease and its neuropsychiatric complications (Table 2). Flavonoids, particularly quercetin and silymarin, have been widely studied for their ability to modulate Nrf2 activity in NAFLD and NASH models. Quercetin, found in various fruits and vegetables, enhances Nrf2 nuclear translocation, increasing HO-1 expression and reducing lipid peroxidation in hepatocytes[76]. Silymarin, the principal bioactive constituent of milk thistle, confers hepatoprotective benefits in NASH by promoting Nrf2 stabilization and inhibiting its Keap1-mediated degradation. This regulatory effect enhances cellular antioxidant capacity and downregulates pro-inflammatory cytokines, including TNF-α[77]. Among alkaloids, berberine, an isoquinoline alkaloid extracted from Berberis species, has shown strong hepatoprotective potential. Berberine suppresses de novo lipogenesis through downregulating the expression of acetyl-CoA carboxylase and fatty acid synthetase thereby alleviating nonalcoholic fatty liver disease[78]. Ginsenosides have been reported to augment the activity of endogenous antioxidant enzymes, suppress ROS generation, and activate adenosine 5’-monophosphate-activated protein kinase (AMPK), thereby attenuating lipid deposition and oxidative injury in hepatic cells[79]. By stimulating the Nrf2/HO-1 signaling cascade, capillin attenuates oxidative stress in hepatic tissue, while concurrently suppressing hepatocyte apoptosis through inhibition of the nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome. Together, these mechanisms contribute to reduced lipid accumulation, oxidative hepatocellular damage, and overall liver injury in metabolic-associated steatohepatitis (MASH) murine models, underscoring its promising therapeutic potential[80]. Baicalin demonstrates hepatoprotective effects by modulating mitochondrial function and suppressing pyroptosis. Study indicate that it activates the Nrf2/HO-1 pathway, leading to reduced NLRP3/caspase-1/GSDMD levels, which alleviates hepatic lipid accumulation and inflammation in MASH mice[81]. Likewise, aloin confers protection in MASH models by upregulating antioxidant defenses, attenuating inflammatory responses, and inhibiting apoptosis, primarily through activation of the Nrf2/HO-1 signaling pathway[82]. Furthermore, flavones derived from hawthorn leaves attenuate oxidative stress and liver inflammation by upregulating Nrf2/HO-1 while suppressing cyclooxygenase 2 overexpression, thereby inhibiting MASH progression[83]. Linalool effectively mitigates high-fat diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) by activating the Nrf2/HO-1 signaling pathway, which suppresses lipid accumulation and oxidative stress[84]. Similarly, wogonoside demonstrates hepatoprotective effects by upregulating the Nrf2/HO-1 pathway to counteract oxidative stress while inhibiting the NF-κB pathway to reduce inflammation. This dual action significantly improves liver mass, liver index, and lipid profiles (low density lipoprotein, triglyceride, total cholesterol) in MASLD mice[85]. Scutellarin alleviates NAFLD by enhancing Nrf2/HO-1 signaling, thereby reducing oxidative stress and improving hepatic function[86,87]. Naringin has been shown to regulate the Nrf2/HO-1 signaling axis while concurrently downregulating the NF-κB/TNF-α inflammatory pathway and inhibiting hepatic triglyceride biosynthesis, thereby exerting a protective effect against the progression of MASLD[88]. Geniposide exerts protective effects by upregulating Nrf2 expression and increasing HO-1 protein levels, significantly reducing lipid accumulation in HepG2 cells[18]. Importantly, the lipid-regulatory and antioxidative benefits of genistein are nullified upon Nrf2 silencing, underscoring the pathway’s pivotal role. Furthermore, dehydroabietic acid exerts its activity by directly interacting with Keap1, thereby initiating the Nrf2-ARE signaling cascade and enhancing the transcription of antioxidant effectors such as HO-1, GSH, and GPX4. This molecular mechanism effectively suppresses ROS accumulation and lowers malondialdehyde levels, ultimately mitigating MASLD progression in high-fat diet models (Table 3)[89].

Table 2 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate alcoholic liver disease.
Monomers
Disease models
Mechanisms
Role
Ref.
QuercetinALDInduces p62 expression, inhibits the binding of Keap1 to Nrf2ImproveTseng et al[116]
SilymarinALDReduces TGF-β1 and 4-HYP levels, suppressing oxidative injuryImproveChen et al[117]
CurcuminALDSuppress p53 expression, enhances Nrf2 nuclear translocationImproveYu et al[118]
GinsenosidesALDReduces oxidative stress and liver inflammationImproveChen et al[119]
BaicalinALDAntioxidant and anti-inflammatoryImproveYang et al[120]
PolysaccharidesALDRegulating oxidative stress and improve alcoholic liver injury by inhibiting the production of inflammatory factorsImproveRoehlen et al[121]
Oleanolic acidALDSuppress the alcohol-induced increasesImproveZhang et al[122]
CAEALDAntioxidant, anti-inflammatory, and anti-apoptoticImproveParola and Pinzani[123]
Table 3 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate drug-induced liver injury.
Monomers
Disease models
Mechanisms
Role
Ref.
IsorhamnetinDILIReduces oxidative stress, inflammation, and pyroptosisImproveForner et al[134]
DihydromyricetinDILIReduces apoptosis and oxidative stressImproveGanesan and Kulik[135]
CurcuminDILIAlleviate hepatic inflammationImproveYang et al[136]
BerberineDILIAlleviate hepatic inflammationImprove
ResveratrolDILIMitigate oxidative stress, and mitochondrial dysfunctionImproveXu et al[137]
GinsenosidesDILIReduces apoptosis and ROSImproveHayes and McMahon[138]
AndrographolideDILIDecreases MDA and ROSImproveHallis et al[139]
Astragaloside IVDILIReduces inflammationImproveLoboda et al[140]
Salvianolic acid CDILIAttenuates oxidative stress, inflammation, and apoptosisImproveLohitesh et al[141]
Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate ALD

Nrf2/HO-1 signaling pathway in ALD: ALD encompasses a continuum of hepatic disorders resulting from chronic excessive alcohol intake, spanning from hepatic steatosis characterized by intracellular fat deposition to more severe pathologies such as alcoholic hepatitis, progressive fibrosis, cirrhosis, and ultimately HCC[90]. Chronic alcohol intake leads to metabolic imbalances and oxidative stress, which play a central role in ALD pathogenesis[91]. In hepatocytes, ethanol undergoes metabolic processing predominantly via alcohol dehydrogenase and the cytochrome P450 isoenzyme CYP2E1. This enzymatic activity leads to overproduction of ROS, which in turn induce oxidative damage to essential cellular macromolecules, including lipids, proteins, and nucleic acids[92]. ROS also impair mitochondrial function, contributing to energy deficits and apoptosis, which accelerates hepatic inflammation and fibrosis[93]. One of the key regulators of oxidative stress and inflammation in ALD is the Nrf2/HO-1 signaling pathway[94]. During oxidative stress induced by alcohol metabolism, ROS-mediated modifications of Keap1 cysteine residues disrupt its interaction with Nrf2, allowing Nrf2 to escape degradation, translocate into the nucleus and be activated[94]. In ALD, activation of Nrf2/HO-1 has been shown to counteract ethanol-induced hepatotoxicity by reducing oxidative stress, suppressing pro-inflammatory cytokine production, and preventing fibrosis through inhibition of hepatic stellate cell activation[95]. However, in chronic and advanced ALD, prolonged activation of Nrf2 may contribute to metabolic reprogramming that favors lipid accumulation and fibrosis[96].

Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate ALD: Among herbal monomers, flavonoids represent a well-characterized and widely investigated phytochemical class, recognized for their potent antioxidant capacity and liver-protective properties in the context of ALD. Quercetin, a flavonoid found in onions and citrus fruits, has been shown to upregulate Nrf2 expression and enhance HO-1 activation, thereby reducing oxidative stress, inflammatory cytokine production, and protecting against ethanol-induced oxidative damage[97]. Similarly, silymarin, a polyphenolic compound extracted from milk thistle (Silybum marianum), has demonstrated potent hepatoprotective effects by preventing ethanol-induced lipid peroxidation and inflammation through Nrf2/HO-1 activation[98]. Curcumin, the active polyphenolic compound in turmeric (Curcuma longa). Curcumin has been demonstrated to facilitate the nuclear translocation of Nrf2 and upregulate the expression of HO-1, while concurrently downregulating p53 expression. These coordinated molecular actions contribute to the attenuation of oxidative stress and hepatic damage induced by ethanol exposure[99]. Ginsenosides, derived from Panax ginseng, have been reported to activate the Sirt6/Nrf2/HO-1 axis, reducing oxidative stress and liver inflammation[100]. Furthermore, baicalin has been shown to inhibit NF-κB activation while upregulating Nrf2/HO-1, offering dual antioxidant and anti-inflammatory effects against ALD[101]. Poria cocos polysaccharides have demonstrated hepatoprotective effects by enhancing HO-1 expression and reducing ethanol-induced hepatocyte ferroptosis[102]. Other herbal monomers, such as oleanolic acid, polymethoxy flavonoid-containing citrus aurantium extract have also shown promise in ALD therapy. Oleanolic acid has been reported to suppress the alcohol-induced increases in intestinal permeability, making it for a hepatoprotection agent[103]. Extracts from Citrus aurantium have been shown to promote the phosphorylation of both AMPK and Nrf2 pathways, thereby exerting multifaceted protective effects including antioxidant, anti-inflammatory, and anti-apoptotic activities against liver injury induced by ethanol exposure[104].

Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate drug-induced liver injury

Nrf2/HO-1 signaling pathway in drug-induced liver injury: Drug-induced liver injury (DILI) is a major clinical concern and one of the most frequent causes of acute liver failure worldwide[105]. DILI occurs due to hepatotoxicity caused by pharmaceuticals, herbal remedies, or dietary supplements[106]. Drugs most frequently implicated in DILI include acetaminophen (paracetamol), various classes of antibiotics, nonsteroidal anti-inflammatory drugs, and certain anticonvulsants, notably sodium valproate[107]. The hepatotoxic effects of these agents are mediated through diverse pathogenic pathways, notably oxidative stress, mitochondrial impairment, and inflammatory responses. Among these, oxidative stress is recognized as a central driver in the development of DILI[108]. Hepatotoxic drugs often induce excessive production of ROS, which overwhelms the liver’s intrinsic antioxidant defenses, leading to lipid peroxidation, protein oxidation, and DNA damage[109]. Acetaminophen, for instance, is metabolized into the toxic intermediate N-acetyl-p-benzoquinone imine, which depletes GSH and causes hepatocyte necrosis[110]. Additionally, mitochondrial dysfunction plays a critical role in drug-induced hepatotoxicity, as mitochondrial permeability transition pore opening can trigger apoptosis and necrosis[111]. Activation of the Nrf2/HO-1 signaling cascade serves as a pivotal defense mechanism against DILI, primarily by upregulating phase II detoxification enzymes and a suite of antioxidant proteins such as HO-1, glutathione S-transferases, nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (NQO1), and SOD[112]. HO-1, in particular, catalyzes the breakdown of heme into biliverdin, CO, and free iron, exerting cytoprotective effects by reducing oxidative stress, inflammation, and apoptosis[54]. In addition to its antioxidant properties, the Nrf2/HO-1 axis plays a pivotal role in modulating inflammation in DILI. Moreover, Nrf2 activation mitigates endoplasmic reticulum stress and ferroptosis, both of which contribute to hepatocyte injury in DILI[113-115]. In light of its cytoprotective functions, modulation of the Nrf2/HO-1 signaling axis has emerged as a compelling therapeutic approach for the prevention and attenuation of DILI (Table 4).

Table 4 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate hepatitis C virus.
Monomers
Disease models
Mechanisms
Role
Ref.
AndrographolideHCVIncreases biliverdin levelsImproveNarożna et al[150]
CelastrolHCVEnhances antiviral interferon responses, suppresses NS3/4A protease activityImproveHassan et al[151]
LucidoneHCVIncreases biliverdin levelsImproveSun et al[152]
SulforaphaneHCVEnhances IFN responses, suppresses NS3 protease activityImproveFu et al[153]
CurcuminHCVInduces HO-1, inhibits PI3-AKT pathwayImproveChopra and Dhingra[154]

Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate DILI: Isorhamnetin, a naturally occurring bioflavonoid present in medicinal plants such as Hippophae rhamnoides L. and Ginkgo biloba L., has been shown to activate Nrf2 signaling and enhance HO-1 enzymatic activity, thereby attenuating oxidative stress and inflammatory responses in models of acetaminophen-induced liver injury[116]. Dihydromyricetin, a flavonoid derived from Ampelopsis grossedentata, has been shown to ameliorate sodium valproate-induced liver injury by modulating the Keap1/Nrf2/HO-1 and NF-κB/caspase-3 pathways, reducing apoptosis and oxidative stress[117]. Curcumin combined with berberine protects against acetaminophen (APAP)-induced DILI by alleviating hepatic inflammation through NF-κB inhibition, potentially mediated by PI3K/Akt and peroxisome proliferators-activated receptors-γ signaling pathways[118]. Resveratrol, a polyphenol found in grapes and red wine, has been shown to effectively mitigated liver injury, oxidative stress, and mitochondrial dysfunction by modulating the Nrf2-mediated antioxidant pathway and restoring GSH synthesis[119]. Ginsenosides from Panax ginseng enhance Nrf2 activation, increase HO-1 expression, and reduce inflammatory cytokine levels in liver injury models[120]. Andrographolide, a diterpenoid lactone from Andrographis paniculata, has been shown to suppress oxidative stress and inflammation in DILI through Nrf2/HO-1 modulation[121]. Astragaloside IV, a major bioactive component of Astragalus membranaceus, has been reported to reduce inflammation accumulation via Nrf2/HO-1 activation[122]. Similarly, salvianolic acid C from Salvia miltiorrhiza has been found to alleviate APAP-induced hepatocyte damage by reducing mitochondrial oxidative stress, suppressing inflammatory responses, and inhibiting caspase-mediated apoptosis through modulation of the Keap1/Nrf2/HO-1 signaling pathway[123].

Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate hepatitis C virus

Nrf2/HO-1 signaling pathway in hepatitis C virus: Hepatitis C virus (HCV)-induced viral hepatitis continues to pose a significant global public health burden, serving as a major etiological factor in the development of chronic liver disease, hepatic cirrhosis, and HCC[124]. HCV infections trigger persistent inflammation, oxidative stress, and hepatocyte injury, which promote fibrosis and eventual liver failure[125]. The Nrf2/HO-1 signaling pathway has been identified as a critical regulator of oxidative stress responses in viral hepatitis, modulating both antiviral immunity and hepatoprotective mechanisms. HCV infections disrupt redox homeostasis by increasing ROS production, which exacerbates inflammation and viral replication[126]. HCV, in particular, induces mitochondrial dysfunction and lipid peroxidation, leading to chronic oxidative stress and hepatic steatosis[127]. During hepatitis B virus and HCV infections, the activation of Nrf2-a central transcriptional regulator of cellular antioxidant responses is disrupted as a result of viral interference with its Keap1-dependent degradation pathway[128]. However, certain viral proteins, such as the nonstructural (NS) protein 3/NS protein 5A proteins in HCV, paradoxically upregulate Nrf2, leading to an adaptive response that enhances viral persistence while promoting liver disease progression[129]. CO generated by HO-1 has been shown to inhibit hepatitis B virus replication by downregulating viral transcription[130]. Similarly, HO-1 activation inhibits HCV replication by limiting oxidative damage and preventing viral protein accumulation (Table 5)[131].

Table 5 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate liver fibrosis and cirrhosis.
Monomers
Disease models
Mechanisms
Role
Ref.
CurcuminCirrhosisReduces collagen I depositionImproveYatoo et al[162]
CurcuminFibrosisReduces oxidative stress, inflammatory and fibrotic markersImproveSailo et al[163]
Pomegranate extractFibrosisReduces oxidative stress, inflammatory and fibrotic markersImproveSailo et al[163]
HyperosideFibrosisReduces oxidative stress, restores antioxidant enzyme activitiesImproveManawy et al[164]
Schisandrin BFibrosisMitigates oxidative stress, suppresses HSC activationImproveRobledinos-Antón et al[165]
TanshinolFibrosisReduces oxidative stress, MDA, inflammatoryImproveKundrapu and Malla[166]
Salvianolic acid AFibrosisInhibits inflammation and oxidative stressImproveWu et al[167]
Asiatic acidFibrosisReduces oxidative stressImproveWang et al[168]

Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate HCV: Andrographolide activates Nrf2 signaling and enhances HO-1 expression, thereby reducing oxidative stress and inhibiting HCV replication[132]. Celastrol has been shown to suppress HCV replication by upregulating HO-1 expression via activation of the c-Jun N-terminal kinase/Nrf2 signaling pathway, thereby augmenting interferon-mediated antiviral responses and inhibiting the enzymatic activity of the viral NS3/4A protease[133]. Lucidone exhibited potent anti-HCV activity by stimulating Nrf2-mediated HO-1 expression, which increased biliverdin levels to enhance antiviral interferon responses inhibit HCV NS3/4A protease activity, suppress HCV RNA replication[134]. Sulforaphane significantly inhibits HCV replication by activating the PI3K/Nrf2/HO-1 pathway, which enhances interferon responses and suppresses NS3 protease activity[135]. Curcumin demonstrates potent anti-HCV activity by dose-dependently inhibiting HCV replication through HO-1 induction and suppression of the PI3K-AKT pathway. While curcumin also inhibits extracellular regulated protein kinases and NF-κB signaling, these effects slightly increase HCV protein expression, highlighting the need for careful consideration when using curcumin as an adjuvant in anti-HCV therapy[136].

Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate liver fibrosis and cirrhosis

Nrf2/HO-1 signaling pathway in liver fibrosis and cirrhosis: Chronic liver fibrosis and cirrhosis represent progressive pathological conditions marked by abnormal accumulation of extracellular matrix components, particularly collagen, as a consequence of sustained hepatic insults arising from viral hepatitis, metabolic dysregulation, alcohol abuse, or hepatotoxic drug exposure[137]. Fibrosis is a wound-healing response, and its unchecked progression results in cirrhosis, leading to severe liver dysfunction and an increased risk of HCC[138]. Hepatic stellate cells are central to fibrosis development as they transition from a quiescent state to activated myofibroblast-like cells, secreting excessive extracellular matrix components that compromise liver architecture and function[139]. This fibrotic process is largely driven by oxidative stress, pro-inflammatory signaling, and the TGF-β/Smad pathway, which promotes myofibroblast differentiation and collagen synthesis[140]. The Nrf2/HO-1 signaling axis plays a pivotal role in counteracting hepatic fibrogenesis. Activation of Nrf2 has been demonstrated to downregulate key profibrotic genes, including α-smooth muscle actin, collagen type I, and tissue inhibitor of metalloproteinases-1, thereby restraining extracellular matrix deposition and fibrotic progression[141]. The upregulation of HO-1 exerts anti-fibrotic effects by modulating multiple pathways involved in fibrosis. HO-1-generated CO and bilirubin have been shown to suppress NF-κB activity, reducing inflammation and cytokine production[142]. HO-1 also influences iron homeostasis, preventing iron overload-induced oxidative stress, which is another major driver of fibrotic progression (Table 6)[143].

Table 6 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate hepatocellular carcinoma.
Monomers
Disease models
Mechanisms
Role
Ref.
CurcuminHCCReduces oxidative damage and inflammationImproveKhalil et al[178]
ResveratrolHCCAgainst oxidative stressImproveAmirshahrokhi and Niapour[179]
BerberineHCCReduces hepatic triglyceride accumulation and oxidative stressImproveBellaver et al[181]
Tanshinone IIAHCCReduces oxidative stress markers and enhances antioxidant defensesImproveZhao et al[182]
GinsenosidesHCCInhibits inflammasomesImproveGao et al[183]
BrusatolHCCMediates ferroptosisImproveGörg et al[184]
Oleanolic acid oxime derivativesHCCReduces cell cycle, apoptosis, and proliferationImproveNavarro and Esteras[185]
EmodinHCCSuppresses cell proliferation, invasion, and angiogenesisImproveWang et al[186]

Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate liver fibrosis and cirrhosis: Curcumin effectively reversed carbon tetrachloride-induced liver cirrhosis in hamsters by reducing collagen I deposition, normalizing hepatic function, and increasing the Nrf-2/NF-κB message RNA ratio[144]. Additionally, curcumin and pomegranate extract, both individually and in combination, significantly attenuated thioacetamide-induced liver fibrosis in rats by modulating Nrf2/HO-1, NF-κB, and TGF-β/Smad3 signaling pathways, as evidenced by improved liver function, reduced oxidative stress, and decreased inflammatory and fibrotic markers[145]. Hyperoside has been shown to mitigate liver injury induced by carbon tetrachloride through attenuation of oxidative stress, restoration of endogenous antioxidant enzyme function, and improvement of histopathological alterations. These protective effects are partly mediated by promoting Nrf2 translocation into the nucleus, thereby upregulating antioxidant defenses and enhancing phase II detoxification enzyme activity[146]. Schisandrin B activates nuclear Nrf2, thereby mitigating oxidative stress-induced hepatocyte injury. It also suppresses hepatic stellate cell activation by inhibiting the TGF-β/Smad signaling pathway, effectively alleviating liver fibrosis[147]. Tanshinol enhances SOD and glutathione peroxidase levels while reducing malondialdehyde levels through the Nrf2/HO-1 pathway, countering oxidative stress. Additionally, it inhibits the NF-κB pathway, reducing inflammatory factors such as TGF-β and TNF-α, and significantly lowers serum markers of liver injury and fibrosis[148]. Salvianolic acid A exerts antifibrotic effects in carbon tetrachloride-induced liver injury by enhancing the activities of antioxidant enzymes such as SOD and glutathione peroxidase, while simultaneously reducing malondialdehyde levels. These effects are mediated through modulation of the Nrf2/HO-1 signaling pathway, leading to attenuation of oxidative stress and inflammatory responses[149]. Asiatic acid activates the Nrf2/ARE pathway to upregulate HO-1 and NQO1, countering oxidative stress, while inhibiting NF-κB/IκBα and Janus tyrosine kinase 1/signal transducer and activator of transcription 3 pathways to reduce inflammation and hepatic stellate cell activation, thereby preventing hepatic fibrosis progression[150].

Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate HCC

Nrf2/HO-1 signaling pathway in HCC: HCC, the predominant form of primary liver malignancy, represents a major contributor to global cancer-associated mortality. It typically develops in the setting of chronic liver disease, particularly liver fibrosis and cirrhosis, which result from persistent inflammation, oxidative stress, and metabolic disturbances[151]. Major risk factors for HCC include chronic hepatitis B and C infections, alcoholic and NAFLD/NASH, aflatoxin exposure, and metabolic syndromes[152]. At the onset of liver disease, the Nrf2/HO-1 pathway functions as a crucial defense mechanism by mitigating oxidative damage, suppressing pro-inflammatory cytokines, and promoting DNA repair mechanisms[153]. During early hepatocarcinogenesis, Nrf2-mediated induction of HO-1, NQO1, and GPX4 plays a protective role by neutralizing ROS, thereby preventing oxidative DNA damage and oncogenic mutations[11]. HO-1, in particular, exerts anti-apoptotic and cytoprotective effects by generating CO and bilirubin, which possess strong antioxidant and anti-inflammatory properties[11]. However, as HCC progresses, persistent Nrf2 activation can become detrimental. Many HCC tumors exhibit Keap1 mutations, leading to constitutive Nrf2 activation, which promotes metabolic reprogramming, drug resistance, and tumor growth[154]. High levels of Nrf2 activity enhance glucose metabolism via the pentose phosphate pathway, providing increased nicotinamide adenine dinucleotide phosphate and GSH production, which supports cancer cell survival[155]. Furthermore, sustained HO-1 overexpression is associated with enhanced angiogenesis and immune evasion, allowing tumors to thrive in oxidative and inflammatory environments[156]. One of the most significant challenges in HCC treatment is chemoresistance, where tumor cells become resistant to sorafenib, cisplatin, and doxorubicin-the frontline chemotherapeutic agents[157]. Evidence suggests that excessive activation of the Nrf2/HO-1 pathway enhances the expression of drug efflux transporters, including members of the multidrug resistance-associated protein family, thereby limiting intracellular accumulation of chemotherapeutic agents in HCC cells[158]. Despite its role in tumor progression, selective modulation of Nrf2/HO-1 remains a promising therapeutic approach.

Natural herbal monomers targeting the Nrf2/HO-1 signaling pathway to modulate HCC: Curcumin, a polyphenol from Curcuma longa, has been extensively studied for its Nrf2-regulating properties. In HCC models, curcumin activates Nrf2 to protect hepatocytes from oxidative DNA damage and inflammation, thereby preventing malignant transformation[159]. Resveratrol, a polyphenol found in grapes, has been shown to modulate Nrf2 activity in a dose-dependent manner. At low concentrations, resveratrol activates Nrf2/HO-1, offering protective effects against oxidative stress-induced liver damage[160]. However, at higher doses, resveratrol suppresses HO-1 expression, reducing HCC cell proliferation, inducing apoptosis, and enhancing chemosensitivity[161]. Berberine reduces hepatic triglyceride accumulation and oxidative stress in hepatoma cells by promoting Nrf2 activation and nuclear distribution, while suppressing Nox2-dependent and mitochondrial ROS production through downregulation of complex I and III expression[162]. Tanshinone IIA confers hepatoprotective effects in HCC by concurrently suppressing the PI3K/Akt signaling cascade and activating the Nrf2/HO-1 pathway, resulting in diminished oxidative stress biomarkers and upregulation of endogenous antioxidant defense mechanisms[163]. Recent studies have demonstrated that ginsenosides increase the susceptibility of HCC cells to apoptosis, making them potential adjuvants in combination therapy[164]. Brusatol, a quassinoid compound derived from Brucea javanica, has been shown to potentiate chemotherapeutic efficacy by specifically inhibiting Nrf2 signaling, thereby reversing sorafenib resistance in HCC cells and facilitating ferroptotic cell death through downregulation of the Nrf2-driven antioxidant defense system[165]. Oleanolic acid oxime derivatives significantly activate Nrf2 in HepG2 cells, inducing cell cycle arrest, apoptosis, and reduced proliferation[166]. Emodin demonstrates significant anticancer activity against HCC by reducing hepatic nodules, suppressing proliferation, invasion, and angiogenesis, while enhancing oxidative stress defense and tissue homeostasis[167].

CHALLENGES, LIMITATIONS, AND FUTURE DIRECTIONS IN TARGETING THE NRF2/HO-1 PATHWAY FOR LIVER DISEASES AND NEUROPSYCHIATRIC DISORDERS
Challenges in translating preclinical research to clinical use

The use of natural herbal monomers in regulating the Nrf2/HO-1 pathway has shown promising hepatoprotective effects in various preclinical studies[168]. However, several key challenges hinder the translation of these findings into clinical practice[169]. One of the foremost challenges is the low bioavailability of many herbal monomers, such as curcumin and resveratrol, which exhibit poor absorption, rapid metabolism, and limited systemic circulation in vivo[170-172]. Another major challenge is the lack of standardized dosages and formulations in clinical trials. Unlike synthetic pharmaceuticals, natural herbal monomers are often sourced from different plant species, leading to variations in purity, concentration, and pharmacokinetics[173]. Additionally, off-target effects and safety concerns surrounding Nrf2 overactivation present another critical challenge[174]. While Nrf2 activation is beneficial in counteracting oxidative stress and inflammation, sustained activation has been associated with increased resistance to apoptosis and enhanced survival of precancerous cells, potentially promoting tumor progression[175].

Potential for combination therapies

Given the complex pathophysiology of liver diseases, combination therapies that integrate herbal monomers with existing pharmacological agents may enhance therapeutic outcomes[176]. Natural compounds such as curcumin, baicalin, and ginsenosides have demonstrated synergistic effects when combined with conventional hepatoprotective drugs[177]. For instance, curcumin has been shown to enhance the efficacy of silymarin, a widely used hepatoprotective drug, by modulating oxidative stress and inflammatory pathways through the Nrf2/HO-1 axis[178]. Furthermore, herbal monomers may also serve as chemosensitizers, enhancing the response to existing anti-fibrotic or anti-inflammatory drugs[179,180]. For example, resveratrol has been reported to potentiate the anti-inflammatory effects of pirfenidone by modulating TGF-β signaling[181]. Another emerging strategy is the use of Nrf2 activators in combination with immune checkpoint inhibitors for the treatment of HCC, as this approach may reduce oxidative stress-mediated immune suppression while preserving hepatocyte function[182].

Future research directions: Targeting the Nrf2/HO-1 pathway for liver diseases and neuropsychiatric complications

The future of herbal monomers in liver disease therapy through the Nrf2/HO-1 pathway lies in overcoming the current limitations and advancing research in the following key areas: (1) Development of advanced drug delivery systems: The integration of nanotechnology with herbal medicine has led to nano-drug formulations that improve the solubility, bioavailability, and targeted delivery of natural compounds. Lipid nanoparticles, polymeric micelles, and liposomal encapsulation have been successfully employed to enhance the pharmacokinetics of quercetin, berberine, and ginsenosides[183-185]; (2) Personalized medicine and biomarker-driven approaches: Interindividual variability in Nrf2 genetic polymorphisms significantly influences responsiveness to herbal monomers. For instance, NFE2 L2 mutations have been linked to differences in antioxidant response capacity, potentially altering the effectiveness of Nrf2-targeted therapies[186]. Identifying biomarkers of Nrf2 activation may enable personalized treatment strategies, ensuring that patients with specific genetic predispositions receive tailored interventions; (3) Long-term safety and efficacy trials: While short-term studies have demonstrated the hepatoprotective potential of herbal monomers, longitudinal clinical trials are required to establish long-term safety profiles. Comparative studies assessing the efficacy of herbal monomers against standard-of-care therapies will be crucial in determining their clinical utility[187]; and (4) Expanding the scope beyond hepatic disorders: Given the overlapping molecular mechanisms involved in oxidative stress and inflammation across different organ systems, herbal Nrf2 activators may hold therapeutic potential in broader disease contexts, providing a multi-targeted strategy for chronic disease management[188,189].

Dual roles of Nrf2 in hepatic protection and pathology

Under physiological conditions or early stages of liver injury, Nrf2 activation plays a crucial role in maintaining redox homeostasis, reducing oxidative damage, and promoting tissue repair.

However, in advanced liver diseases such as HCC, Nrf2 may paradoxically facilitate tumor progression. Persistent or constitutive Nrf2 activation often driven by loss-of-function mutations in Keap1 or epigenetic silencing of negative regulators-enhances tumor cell survival, detoxification, and proliferation.

Additionally, Nrf2-driven transcription of anti-apoptotic genes and adenosine triphosphate-binding cassette drug transporters (e.g., ABCG2) has been linked to chemoresistance to sorafenib, the first-line systemic therapy for HCC.

These findings highlight the dualistic nature of Nrf2, functioning as a protector in inflammatory settings but potentially contributing to carcinogenesis and therapeutic resistance when dysregulated. As such, therapeutic strategies targeting Nrf2 should emphasize context-specific modulation, taking into account disease stage, genetic background, and oncogenic potential.

Future drug development may benefit from transient or localized activation of Nrf2, or combination therapies designed to avoid sustained oncogenic signaling, particularly in high-risk populations.

CONCLUSION

This review comprehensively explored the pivotal role of the Nrf2/HO-1 signaling pathway in both liver diseases and HE, emphasizing its therapeutic potential in addressing oxidative stress, inflammation, and fibrosis, while also mitigating neuropsychiatric symptoms. Given the escalating burden of liver diseases worldwide, it is increasingly crucial to develop therapeutic strategies that not only alleviate hepatic damage but also address the associated neuropsychiatric complications such as cognitive decline, mood disorders, and motor dysfunction. The Nrf2/HO-1 axis, as a master regulator of antioxidant responses, detoxification, and immune modulation, represents a critical therapeutic target for both hepatic and neurological pathologies. This review provided an in-depth overview of the structural and functional characteristics of Nrf2 and HO-1, emphasizing their physiological significance and the molecular mechanisms governing their activation. Under homeostatic conditions, Nrf2 activity is tightly suppressed by its cytoplasmic repressor Keap1; however, in response to oxidative or electrophilic stress, Nrf2 is rapidly stabilized and translocated to the nucleus, where it orchestrates the expression of a spectrum of cytoprotective genes. Among these, HO-1 acts as a pivotal downstream effector by catalyzing the degradation of heme into biliverdin, CO, and free iron metabolites known to restore neurotransmitter equilibrium and promote synaptic plasticity, thereby exerting neuroprotective and anti-inflammatory effects. Notably, dysregulation of the Nrf2/HO-1 axis has been implicated in both beneficial and detrimental outcomes in the context of liver pathologies and HE-related neuropsychiatric manifestations, highlighting the critical importance of fine-tuned modulation of this pathway to harness therapeutic benefit while avoiding unintended consequences. Focusing on liver pathophysiology, we explored how Nrf2/HO-1 can suppress inflammation, prevent oxidative damage, and regulate hepatic metabolism, thus highlighting its potential as a therapeutic target across a range of liver disease models. A central part of this review was dedicated to the role of natural herbal monomers in modulating the Nrf2/HO-1 pathway. Flavonoids, alkaloids, phenolics, and terpenoids have been shown to activate Nrf2, promote HO-1 expression, and restore hepatic redox balance. Key herbal compounds such as quercetin, silymarin, berberine, curcumin, resveratrol, ginsenosides, and Astragalus polysaccharides have demonstrated significant hepatoprotective effects in both preclinical and clinical studies. However, despite the promising therapeutic potential of these herbal monomers, several challenges remain in translating these findings into clinical applications. Issues such as low bioavailability, lack of standardized formulations, and the long-term effects of sustained Nrf2 activation pose significant hurdles for their clinical adoption. To overcome these challenges, future research should focus on optimizing drug delivery systems, refining dosage protocols, and conducting well-designed clinical trials to validate the efficacy and safety of these compounds. Additionally, advancing personalized medicine approaches by identifying biomarkers of Nrf2 activation could enhance treatment outcomes while minimizing potential adverse effects. Moreover, this review underscores the connection between the Nrf2/HO-1 pathway and HE-associated neuropsychiatric symptoms, a condition characterized by toxic metabolite accumulation and oxidative stress. The Nrf2/HO-1 pathway plays a pivotal role in modulating neuroinflammation, neurotoxicity, and ammonia metabolism in both the liver and brain, highlighting its therapeutic potential in HE management, particularly in ameliorating brain ammonia toxicity, neuroinflammation, and oxidative stress, thus improving cognitive and behavioral outcomes. Although most of the mechanistic evidence for natural herbal monomers stems from preclinical models, emerging clinical data support their therapeutic potential. For instance, curcumin has been evaluated in randomized controlled trials for NAFLD, with phase II studies demonstrating improvements in liver enzymes, steatosis, and inflammatory markers. Similarly, silymarin has been investigated in clinical studies for ALD and chronic hepatitis, showing modest but consistent hepatoprotective effects. Berberine has demonstrated efficacy in NAFLD and metabolic syndrome patients by improving lipid profiles and insulin sensitivity. However, clinical trials specifically targeting HE with these compounds remain scarce, underscoring the need for translational research to bridge this gap. Moving forward, well-designed phase II/III trials in HE and liver-brain axis dysfunction are essential to validate the promising effects observed in experimental models. In conclusion, this review demonstrates that Nrf2/HO-1 activation offers a promising strategy for mitigating oxidative stress, inflammation, and fibrosis while simultaneously addressing neuropsychiatric symptoms in liver diseases. Although herbal monomers targeting this pathway show great potential, further clinical validation is essential to ensure their efficacy, safety, and long-term benefits. By integrating traditional herbal medicine with modern pharmacological research, we believe that the development of safe, effective, and clinically viable Nrf2-targeted therapies will advance the holistic management of liver diseases and their neuropsychiatric complications, offering new hope for patients worldwide.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Psychiatry

Country of origin: China

Peer-review report’s classification

Scientific Quality: Grade B, Grade B

Novelty: Grade C, Grade C

Creativity or Innovation: Grade B, Grade B

Scientific Significance: Grade C, Grade C

P-Reviewer: McGorry PD; Mends-Brew E S-Editor: Fan M L-Editor: A P-Editor: Xu ZH

References
1.  Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol. 2023;79:516-537.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 847]  [Reference Citation Analysis (4)]
2.  Rose CF, Amodio P, Bajaj JS, Dhiman RK, Montagnese S, Taylor-Robinson SD, Vilstrup H, Jalan R. Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy. J Hepatol. 2020;73:1526-1547.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 114]  [Cited by in RCA: 274]  [Article Influence: 54.8]  [Reference Citation Analysis (0)]
3.  Allameh A, Niayesh-Mehr R, Aliarab A, Sebastiani G, Pantopoulos K. Oxidative Stress in Liver Pathophysiology and Disease. Antioxidants (Basel). 2023;12:1653.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 50]  [Cited by in RCA: 136]  [Article Influence: 68.0]  [Reference Citation Analysis (0)]
4.  LeFort KR, Rungratanawanich W, Song BJ. Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction. Cell Mol Life Sci. 2024;81:34.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 42]  [Reference Citation Analysis (0)]
5.  Ochoa-Sanchez R, Tamnanloo F, Rose CF. Hepatic Encephalopathy: From Metabolic to Neurodegenerative. Neurochem Res. 2021;46:2612-2625.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 29]  [Cited by in RCA: 28]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
6.  Mortby ME, Burns R, Eramudugolla R, Ismail Z, Anstey KJ. Neuropsychiatric Symptoms and Cognitive Impairment: Understanding the Importance of Co-Morbid Symptoms. J Alzheimers Dis. 2017;59:141-153.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 25]  [Cited by in RCA: 45]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
7.  Margoni M, Preziosa P, Rocca MA, Filippi M. Depressive symptoms, anxiety and cognitive impairment: emerging evidence in multiple sclerosis. Transl Psychiatry. 2023;13:264.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 49]  [Reference Citation Analysis (0)]
8.  Eastman CL, D'Ambrosio R, Ganesh T. Modulating neuroinflammation and oxidative stress to prevent epilepsy and improve outcomes after traumatic brain injury. Neuropharmacology. 2020;172:107907.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 91]  [Cited by in RCA: 91]  [Article Influence: 18.2]  [Reference Citation Analysis (0)]
9.  Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety. 2013;30:297-306.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 487]  [Cited by in RCA: 585]  [Article Influence: 48.8]  [Reference Citation Analysis (0)]
10.  Chiriac S, Stanciu C, Cojocariu C, Singeap AM, Sfarti C, Cuciureanu T, Girleanu I, Igna RA, Trifan A. Role of ammonia in predicting the outcome of patients with acute-on-chronic liver failure. World J Clin Cases. 2021;9:552-564.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in CrossRef: 14]  [Cited by in RCA: 14]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
11.  Alharbi KS, Almalki WH, Albratty M, Meraya AM, Najmi A, Vyas G, Singh SK, Dua K, Gupta G. The therapeutic role of nutraceuticals targeting the Nrf2/HO-1 signaling pathway in liver cancer. J Food Biochem. 2022;46:e14357.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 21]  [Reference Citation Analysis (0)]
12.  Essam RM, Saadawy MA, Gamal M, Abdelsalam RM, El-Sahar AE. Lactoferrin averts neurological and behavioral impairments of thioacetamide-induced hepatic encephalopathy in rats via modulating HGMB1/TLR-4/MyD88/Nrf2 pathway. Neuropharmacology. 2023;236:109575.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 14]  [Reference Citation Analysis (0)]
13.  Tu W, Wang H, Li S, Liu Q, Sha H. The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases. Aging Dis. 2019;10:637-651.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 490]  [Cited by in RCA: 465]  [Article Influence: 77.5]  [Reference Citation Analysis (0)]
14.  Adelusi TI, Du L, Hao M, Zhou X, Xuan Q, Apu C, Sun Y, Lu Q, Yin X. Keap1/Nrf2/ARE signaling unfolds therapeutic targets for redox imbalanced-mediated diseases and diabetic nephropathy. Biomed Pharmacother. 2020;123:109732.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 49]  [Cited by in RCA: 96]  [Article Influence: 19.2]  [Reference Citation Analysis (0)]
15.  Lu C, Liu Y, Ren F, Zhang H, Hou Y, Zhang H, Chen Z, Du X. HO-1: An emerging target in fibrosis. J Cell Physiol. 2025;240:e31465.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 1]  [Reference Citation Analysis (0)]
16.  Cai X, Hua S, Deng J, Du Z, Zhang D, Liu Z, Khan NU, Zhou M, Chen Z. Astaxanthin Activated the Nrf2/HO-1 Pathway to Enhance Autophagy and Inhibit Ferroptosis, Ameliorating Acetaminophen-Induced Liver Injury. ACS Appl Mater Interfaces. 2022;14:42887-42903.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 7]  [Cited by in RCA: 103]  [Article Influence: 34.3]  [Reference Citation Analysis (0)]
17.  Yang R, Gao W, Wang Z, Jian H, Peng L, Yu X, Xue P, Peng W, Li K, Zeng P. Polyphyllin I induced ferroptosis to suppress the progression of hepatocellular carcinoma through activation of the mitochondrial dysfunction via Nrf2/HO-1/GPX4 axis. Phytomedicine. 2024;122:155135.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 101]  [Reference Citation Analysis (0)]
18.  Shen B, Feng H, Cheng J, Li Z, Jin M, Zhao L, Wang Q, Qin H, Liu G. Geniposide alleviates non-alcohol fatty liver disease via regulating Nrf2/AMPK/mTOR signalling pathways. J Cell Mol Med. 2020;24:5097-5108.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 65]  [Cited by in RCA: 93]  [Article Influence: 18.6]  [Reference Citation Analysis (0)]
19.  Tao YC, Wang YH, Wang ML, Jiang W, Wu DB, Chen EQ, Tang H. Upregulation of microRNA-125b-5p alleviates acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway. Front Immunol. 2022;13:988668.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 9]  [Cited by in RCA: 12]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
20.  Patel M, Singh S. Apigenin Attenuates Functional and Structural Alterations via Targeting NF-kB/Nrf2 Signaling Pathway in LPS-Induced Parkinsonism in Experimental Rats : Apigenin Attenuates LPS-Induced Parkinsonism in Experimental Rats. Neurotox Res. 2022;40:941-960.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 1]  [Cited by in RCA: 22]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
21.  Jia W, Liu J, Hu R, Hu A, Tang W, Li L, Li J. Xiaochaihutang Improves the Cortical Astrocyte Edema in Thioacetamide-Induced Rat Acute Hepatic Encephalopathy by Activating NRF2 Pathway. Front Pharmacol. 2020;11:382.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 11]  [Cited by in RCA: 23]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
22.  Augustyniak A, Bartosz G, Cipak A, Duburs G, Horáková L, Luczaj W, Majekova M, Odysseos AD, Rackova L, Skrzydlewska E, Stefek M, Strosová M, Tirzitis G, Venskutonis PR, Viskupicova J, Vraka PS, Zarković N. Natural and synthetic antioxidants: an updated overview. Free Radic Res. 2010;44:1216-1262.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 170]  [Cited by in RCA: 179]  [Article Influence: 11.9]  [Reference Citation Analysis (0)]
23.  Ruggenenti P. The CARDINAL Trial of Bardoxolone Methyl in Alport Syndrome: When Marketing Interests Prevail over Patients Clinical Needs. Nephron. 2023;147:465-469.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 10]  [Reference Citation Analysis (0)]
24.  Chin MP, Wrolstad D, Bakris GL, Chertow GM, de Zeeuw D, Goldsberry A, Linde PG, McCullough PA, McMurray JJ, Wittes J, Meyer CJ. Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. J Card Fail. 2014;20:953-958.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 111]  [Cited by in RCA: 131]  [Article Influence: 11.9]  [Reference Citation Analysis (0)]
25.  Hooda P, Malik R, Bhatia S, Al-Harrasi A, Najmi A, Zoghebi K, Halawi MA, Makeen HA, Mohan S. Phytoimmunomodulators: A review of natural modulators for complex immune system. Heliyon. 2024;10:e23790.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in RCA: 15]  [Reference Citation Analysis (0)]
26.  Jaiswal Y, Liang Z, Zhao Z. Botanical drugs in Ayurveda and Traditional Chinese Medicine. J Ethnopharmacol. 2016;194:245-259.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 61]  [Cited by in RCA: 52]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
27.  Gugliandolo A, Bramanti P, Mazzon E. Activation of Nrf2 by Natural Bioactive Compounds: A Promising Approach for Stroke? Int J Mol Sci. 2020;21:4875.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 23]  [Cited by in RCA: 55]  [Article Influence: 11.0]  [Reference Citation Analysis (0)]
28.  Kanwugu ON, Glukhareva TV. Activation of Nrf2 pathway as a protective mechanism against oxidative stress-induced diseases: Potential of astaxanthin. Arch Biochem Biophys. 2023;741:109601.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 23]  [Reference Citation Analysis (0)]
29.  Jayasuriya R, Dhamodharan U, Ali D, Ganesan K, Xu B, Ramkumar KM. Targeting Nrf2/Keap1 signaling pathway by bioactive natural agents: Possible therapeutic strategy to combat liver disease. Phytomedicine. 2021;92:153755.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 21]  [Cited by in RCA: 62]  [Article Influence: 15.5]  [Reference Citation Analysis (0)]
30.  Abed DA, Goldstein M, Albanyan H, Jin H, Hu L. Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents. Acta Pharm Sin B. 2015;5:285-299.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 151]  [Cited by in RCA: 243]  [Article Influence: 24.3]  [Reference Citation Analysis (0)]
31.  Suzuki T, Yamamoto M. Molecular basis of the Keap1-Nrf2 system. Free Radic Biol Med. 2015;88:93-100.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 624]  [Cited by in RCA: 774]  [Article Influence: 77.4]  [Reference Citation Analysis (0)]
32.  Ryšavá A, Vostálová J, Rajnochová Svobodová A. Effect of ultraviolet radiation on the Nrf2 signaling pathway in skin cells. Int J Radiat Biol. 2021;97:1383-1403.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 9]  [Cited by in RCA: 35]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
33.  Yang F, Smith MJ. Metal profiling in coronary ischemia-reperfusion injury: Implications for KEAP1/NRF2 regulated redox signaling. Free Radic Biol Med. 2024;210:158-171.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 8]  [Cited by in RCA: 10]  [Article Influence: 10.0]  [Reference Citation Analysis (0)]
34.  Liu S, Pi J, Zhang Q. Signal amplification in the KEAP1-NRF2-ARE antioxidant response pathway. Redox Biol. 2022;54:102389.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 2]  [Cited by in RCA: 230]  [Article Influence: 76.7]  [Reference Citation Analysis (0)]
35.  Walters TS, McIntosh DJ, Ingram SM, Tillery L, Motley ED, Arinze IJ, Misra S. SUMO-Modification of Human Nrf2 at K(110) and K(533) Regulates Its Nucleocytoplasmic Localization, Stability and Transcriptional Activity. Cell Physiol Biochem. 2021;55:141-159.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 19]  [Cited by in RCA: 29]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
36.  Hayes JD, Dayalan Naidu S, Dinkova-Kostova AT. Regulating Nrf2 activity: ubiquitin ligases and signaling molecules in redox homeostasis. Trends Biochem Sci. 2025;50:179-205.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 3]  [Cited by in RCA: 10]  [Article Influence: 10.0]  [Reference Citation Analysis (0)]
37.  Kawai Y, Garduño L, Theodore M, Yang J, Arinze IJ. Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization. J Biol Chem. 2011;286:7629-7640.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 224]  [Cited by in RCA: 280]  [Article Influence: 18.7]  [Reference Citation Analysis (0)]
38.  Liu T, Lv YF, Zhao JL, You QD, Jiang ZY. Regulation of Nrf2 by phosphorylation: Consequences for biological function and therapeutic implications. Free Radic Biol Med. 2021;168:129-141.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 45]  [Cited by in RCA: 112]  [Article Influence: 28.0]  [Reference Citation Analysis (0)]
39.  Kang KW, Lee SJ, Kim SG. Molecular mechanism of nrf2 activation by oxidative stress. Antioxid Redox Signal. 2005;7:1664-1673.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 276]  [Cited by in RCA: 289]  [Article Influence: 14.5]  [Reference Citation Analysis (0)]
40.  Ganner A, Pfeiffer ZC, Wingendorf L, Kreis S, Klein M, Walz G, Neumann-Haefelin E. The acetyltransferase p300 regulates NRF2 stability and localization. Biochem Biophys Res Commun. 2020;524:895-902.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 22]  [Cited by in RCA: 46]  [Article Influence: 9.2]  [Reference Citation Analysis (0)]
41.  Xu JJ, Cui J, Lin Q, Chen XY, Zhang J, Gao EH, Wei B, Zhao W. Protection of the enhanced Nrf2 deacetylation and its downstream transcriptional activity by SIRT1 in myocardial ischemia/reperfusion injury. Int J Cardiol. 2021;342:82-93.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 6]  [Cited by in RCA: 54]  [Article Influence: 13.5]  [Reference Citation Analysis (0)]
42.  Yang X, Park SH, Chang HC, Shapiro JS, Vassilopoulos A, Sawicki KT, Chen C, Shang M, Burridge PW, Epting CL, Wilsbacher LD, Jenkitkasemwong S, Knutson M, Gius D, Ardehali H. Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2. J Clin Invest. 2017;127:1505-1516.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 72]  [Cited by in RCA: 113]  [Article Influence: 14.1]  [Reference Citation Analysis (0)]
43.  Potteti HR, Noone PM, Tamatam CR, Ankireddy A, Noel S, Rabb H, Reddy SP. Nrf2 mediates hypoxia-inducible HIF1α activation in kidney tubular epithelial cells. Am J Physiol Renal Physiol. 2021;320:F464-F474.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 28]  [Cited by in RCA: 36]  [Article Influence: 9.0]  [Reference Citation Analysis (0)]
44.  Chen Y, Jiang Z, Li X. New insights into crosstalk between Nrf2 pathway and ferroptosis in lung disease. Cell Death Dis. 2024;15:841.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 9]  [Reference Citation Analysis (0)]
45.  Wardyn JD, Ponsford AH, Sanderson CM. Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways. Biochem Soc Trans. 2015;43:621-626.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 582]  [Cited by in RCA: 880]  [Article Influence: 88.0]  [Reference Citation Analysis (0)]
46.  Wang Z. Iron regulation in ferroptosis. Nat Cell Biol. 2023;25:515.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 16]  [Reference Citation Analysis (0)]
47.  Song X, Long D. Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases. Front Neurosci. 2020;14:267.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 122]  [Cited by in RCA: 404]  [Article Influence: 80.8]  [Reference Citation Analysis (0)]
48.  Kageyama S, Saito T, Obata M, Koide RH, Ichimura Y, Komatsu M. Negative Regulation of the Keap1-Nrf2 Pathway by a p62/Sqstm1 Splicing Variant. Mol Cell Biol. 2018;38:e00642-e00617.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 48]  [Cited by in RCA: 72]  [Article Influence: 10.3]  [Reference Citation Analysis (0)]
49.  Bae T, Hallis SP, Kwak MK. Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer. Exp Mol Med. 2024;56:501-514.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in RCA: 84]  [Reference Citation Analysis (0)]
50.  Shelley K, Articolo A, Luthra R, Charlton M. Clinical characteristics and management of patients with nonalcoholic steatohepatitis in a real-world setting: analysis of the Ipsos NASH therapy monitor database. BMC Gastroenterol. 2023;23:160.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 6]  [Reference Citation Analysis (0)]
51.  Cotter TG, Rinella M. Nonalcoholic Fatty Liver Disease 2020: The State of the Disease. Gastroenterology. 2020;158:1851-1864.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 411]  [Cited by in RCA: 842]  [Article Influence: 168.4]  [Reference Citation Analysis (2)]
52.  Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15:349-364.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 365]  [Cited by in RCA: 665]  [Article Influence: 95.0]  [Reference Citation Analysis (0)]
53.  Gabbia D, Cannella L, De Martin S. The Role of Oxidative Stress in NAFLD-NASH-HCC Transition-Focus on NADPH Oxidases. Biomedicines. 2021;9:687.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 16]  [Cited by in RCA: 67]  [Article Influence: 16.8]  [Reference Citation Analysis (0)]
54.  Duarte TL, Caldas C, Santos AG, Silva-Gomes S, Santos-Gonçalves A, Martins MJ, Porto G, Lopes JM. Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis. Redox Biol. 2017;11:157-169.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 27]  [Cited by in RCA: 34]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
55.  Lu W, Yang X, Wang B. Carbon monoxide potentiates the effect of corticosteroids in suppressing inflammatory responses in cell culture. Bioorg Med Chem. 2025;120:118092.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in RCA: 1]  [Reference Citation Analysis (0)]
56.  Kim SK, Joe Y, Chen Y, Ryu J, Lee JH, Cho GJ, Ryter SW, Chung HT. Carbon monoxide decreases interleukin-1β levels in the lung through the induction of pyrin. Cell Mol Immunol. 2017;14:349-359.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 18]  [Cited by in RCA: 25]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
57.  Tomaro ML, Batlle AM. Bilirubin: its role in cytoprotection against oxidative stress. Int J Biochem Cell Biol. 2002;34:216-220.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 104]  [Cited by in RCA: 115]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
58.  Wu A, Feng B, Yu J, Yan L, Che L, Zhuo Y, Luo Y, Yu B, Wu D, Chen D. Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis. Redox Biol. 2021;46:102131.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 12]  [Cited by in RCA: 183]  [Article Influence: 45.8]  [Reference Citation Analysis (0)]
59.  Jiang L, Yi R, Chen H, Wu S. Quercetin alleviates metabolic-associated fatty liver disease by tuning hepatic lipid metabolism, oxidative stress and inflammation. Anim Biotechnol. 2025;36:2442351.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 5]  [Reference Citation Analysis (0)]
60.  Kim M, Yang SG, Kim JM, Lee JW, Kim YS, Lee JI. Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells. Int J Mol Med. 2012;30:473-479.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 52]  [Cited by in RCA: 63]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
61.  Li H, Liu NN, Li JR, Dong B, Wang MX, Tan JL, Wang XK, Jiang J, Lei L, Li HY, Sun H, Jiang JD, Peng ZG. Combined Use of Bicyclol and Berberine Alleviates Mouse Nonalcoholic Fatty Liver Disease. Front Pharmacol. 2022;13:843872.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in RCA: 12]  [Reference Citation Analysis (0)]
62.  Kim DE, Chang BY, Jeon BM, Baek JI, Kim SC, Kim SY. SGL 121 Attenuates Nonalcoholic Fatty Liver Disease through Adjusting Lipid Metabolism Through AMPK Signaling Pathway. Int J Mol Sci. 2020;21:4534.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 6]  [Cited by in RCA: 17]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
63.  Li B, Wang R, Wang L, Zhang G, Zhang Y. Capillin protects against non-alcoholic steatohepatitis through suppressing NLRP3 inflammasome activation and oxidative stress. Immunopharmacol Immunotoxicol. 2021;43:778-789.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 8]  [Reference Citation Analysis (0)]
64.  Shi H, Qiao F, Lu W, Huang K, Wen Y, Ye L, Chen Y. Baicalin improved hepatic injury of NASH by regulating NRF2/HO-1/NRLP3 pathway. Eur J Pharmacol. 2022;934:175270.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 28]  [Reference Citation Analysis (0)]
65.  Xu Q, Fan Y, Loor JJ, Liang Y, Lv H, Sun X, Jia H, Xu C. Aloin protects mice from diet-induced non-alcoholic steatohepatitis via activation of Nrf2/HO-1 signaling. Food Funct. 2021;12:696-705.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 7]  [Cited by in RCA: 20]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
66.  Li XD, Chen ZY, Yu JS, Wang DJ, Yan MX. [Effect of total flavones of hawthorn leafonon expression of COX-2/Nrf2 in liver of rats with nonalcoholic steatohepatitis]. Zhongguo Zhong Yao Za Zhi. 2016;41:711-715.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 1]  [Cited by in RCA: 3]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
67.  Tamilmani P, Sathibabu Uddandrao VV, Chandrasekaran P, Saravanan G, Brahma Naidu P, Sengottuvelu S, Vadivukkarasi S. Linalool attenuates lipid accumulation and oxidative stress in metabolic dysfunction-associated steatotic liver disease via Sirt1/Akt/PPRA-α/AMPK and Nrf-2/HO-1 signaling pathways. Clin Res Hepatol Gastroenterol. 2023;47:102231.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 3]  [Cited by in RCA: 14]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
68.  Jiang G, Chen D, Li W, Liu C, Liu J, Guo Y. Effects of wogonoside on the inflammatory response and oxidative stress in mice with nonalcoholic fatty liver disease. Pharm Biol. 2020;58:1177-1183.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 8]  [Cited by in RCA: 18]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
69.  Zhang X, Ji R, Sun H, Peng J, Ma X, Wang C, Fu Y, Bao L, Jin Y. Scutellarin ameliorates nonalcoholic fatty liver disease through the PPARγ/PGC-1α-Nrf2 pathway. Free Radic Res. 2018;52:198-211.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 55]  [Cited by in RCA: 53]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
70.  Fan H, Ma X, Lin P, Kang Q, Zhao Z, Wang L, Sun D, Cheng J, Li Y. Scutellarin Prevents Nonalcoholic Fatty Liver Disease (NAFLD) and Hyperlipidemia via PI3K/AKT-Dependent Activation of Nuclear Factor (Erythroid-Derived 2)-Like 2 (Nrf2) in Rats. Med Sci Monit. 2017;23:5599-5612.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 29]  [Cited by in RCA: 48]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
71.  Pengnet S, Sumarithum P, Phongnu N, Prommaouan S, Kantip N, Phoungpetchara I, Malakul W. Naringin attenuates fructose-induced NAFLD progression in rats through reducing endogenous triglyceride synthesis and activating the Nrf2/HO-1 pathway. Front Pharmacol. 2022;13:1049818.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in RCA: 14]  [Reference Citation Analysis (0)]
72.  Gao G, Xie Z, Li EW, Yuan Y, Fu Y, Wang P, Zhang X, Qiao Y, Xu J, Hölscher C, Wang H, Zhang Z. Dehydroabietic acid improves nonalcoholic fatty liver disease through activating the Keap1/Nrf2-ARE signaling pathway to reduce ferroptosis. J Nat Med. 2021;75:540-552.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 18]  [Cited by in RCA: 81]  [Article Influence: 20.3]  [Reference Citation Analysis (0)]
73.  Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH. ACG Clinical Guideline: Alcoholic Liver Disease. Am J Gastroenterol. 2018;113:175-194.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 446]  [Cited by in RCA: 561]  [Article Influence: 80.1]  [Reference Citation Analysis (0)]
74.  Yan C, Hu W, Tu J, Li J, Liang Q, Han S. Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease. J Transl Med. 2023;21:300.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in RCA: 67]  [Reference Citation Analysis (0)]
75.  Doody EE, Groebner JL, Walker JR, Frizol BM, Tuma DJ, Fernandez DJ, Tuma PL. Ethanol metabolism by alcohol dehydrogenase or cytochrome P(450) 2E1 differentially impairs hepatic protein trafficking and growth hormone signaling. Am J Physiol Gastrointest Liver Physiol. 2017;313:G558-G569.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 20]  [Cited by in RCA: 29]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
76.  Ramos-Tovar E, Muriel P. Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver. Antioxidants (Basel). 2020;9:1279.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 141]  [Cited by in RCA: 179]  [Article Influence: 35.8]  [Reference Citation Analysis (0)]
77.  Zhao N, Guo FF, Xie KQ, Zeng T. Targeting Nrf-2 is a promising intervention approach for the prevention of ethanol-induced liver disease. Cell Mol Life Sci. 2018;75:3143-3157.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 52]  [Cited by in RCA: 60]  [Article Influence: 8.6]  [Reference Citation Analysis (0)]
78.  Diluzio NR. Prevention of the Acute Ethanol-Induced Fatty Liver by the Simultaneous Administration of Antioxidants. Life Sci (1962). 1964;3:113-118.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 88]  [Cited by in RCA: 80]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
79.  Yeligar SM, Machida K, Kalra VK. Ethanol-induced HO-1 and NQO1 are differentially regulated by HIF-1alpha and Nrf2 to attenuate inflammatory cytokine expression. J Biol Chem. 2010;285:35359-35373.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 101]  [Cited by in RCA: 128]  [Article Influence: 8.5]  [Reference Citation Analysis (0)]
80.  Lamlé J, Marhenke S, Borlak J, von Wasielewski R, Eriksson CJ, Geffers R, Manns MP, Yamamoto M, Vogel A. Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology. 2008;134:1159-1168.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 149]  [Cited by in RCA: 166]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]
81.  Ji LL, Sheng YC, Zheng ZY, Shi L, Wang ZT. The involvement of p62-Keap1-Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity. Free Radic Biol Med. 2015;85:12-23.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 117]  [Cited by in RCA: 137]  [Article Influence: 13.7]  [Reference Citation Analysis (0)]
82.  Abu-Risha SE, Sokar SS, Elbohoty HR, Elsisi AE. Combined carvacrol and cilostazol ameliorate ethanol-induced liver fibrosis in rats: Possible role of SIRT1/Nrf2/HO-1 pathway. Int Immunopharmacol. 2023;116:109750.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 14]  [Reference Citation Analysis (0)]
83.  Lu C, Xu W, Zhang F, Shao J, Zheng S. Nrf2 Knockdown Disrupts the Protective Effect of Curcumin on Alcohol-Induced Hepatocyte Necroptosis. Mol Pharm. 2016;13:4043-4053.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 63]  [Cited by in RCA: 83]  [Article Influence: 9.2]  [Reference Citation Analysis (0)]
84.  Pan Z, Guo J, Tang K, Chen Y, Gong X, Chen Y, Zhong Y, Xiao X, Duan S, Cui T, Wu X, Zhong Y, Yang X, Shen C, Gao Y. Correction to "Ginsenoside Rc Modulates SIRT6-NRF2 Interaction to Alleviate Alcoholic Liver Disease". J Agric Food Chem. 2023;71:20402-20404.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 1]  [Reference Citation Analysis (0)]
85.  He P, Wu Y, Shun J, Liang Y, Cheng M, Wang Y. Baicalin Ameliorates Liver Injury Induced by Chronic plus Binge Ethanol Feeding by Modulating Oxidative Stress and Inflammation via CYP2E1 and NRF2 in Mice. Oxid Med Cell Longev. 2017;2017:4820414.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 39]  [Cited by in RCA: 51]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
86.  Zhou X, Wang J, Zhou S. Poria cocos polysaccharides improve alcoholic liver disease by interfering with ferroptosis through NRF2 regulation. Aging (Albany NY). 2024;16:6147-6162.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 3]  [Reference Citation Analysis (0)]
87.  Byun HG, Lee JK. Chlorella ethanol extract induced phase II enzyme through NFE2L2 (nuclear factor [erythroid-derived] 2-like 2, NRF2) activation and protected ethanol-induced hepatoxicity. J Med Food. 2015;18:182-189.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 11]  [Cited by in RCA: 13]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
88.  Choi BK, Kim TW, Lee DR, Jung WH, Lim JH, Jung JY, Yang SH, Suh JW. A polymethoxy flavonoids-rich Citrus aurantium extract ameliorates ethanol-induced liver injury through modulation of AMPK and Nrf2-related signals in a binge drinking mouse model. Phytother Res. 2015;29:1577-1584.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 37]  [Cited by in RCA: 46]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
89.  Kumachev A, Wu PE. Drug-induced liver injury. CMAJ. 2021;193:E310.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 3]  [Cited by in RCA: 22]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
90.  Guo K, van den Beucken T. Advances in drug-induced liver injury research: in vitro models, mechanisms, omics and gene modulation techniques. Cell Biosci. 2024;14:134.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 6]  [Reference Citation Analysis (0)]
91.  Björnsson ES. Hepatotoxicity by Drugs: The Most Common Implicated Agents. Int J Mol Sci. 2016;17:224.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 131]  [Cited by in RCA: 177]  [Article Influence: 19.7]  [Reference Citation Analysis (0)]
92.  Donato M, Tolosa L. High-Content Screening for the Detection of Drug-Induced Oxidative Stress in Liver Cells. Antioxidants (Basel). 2021;10:106.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 15]  [Cited by in RCA: 33]  [Article Influence: 8.3]  [Reference Citation Analysis (0)]
93.  Jaeschke H, McGill MR, Ramachandran A. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev. 2012;44:88-106.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 563]  [Cited by in RCA: 687]  [Article Influence: 52.8]  [Reference Citation Analysis (0)]
94.  Bender RP, Lindsey RH Jr, Burden DA, Osheroff N. N-acetyl-p-benzoquinone imine, the toxic metabolite of acetaminophen, is a topoisomerase II poison. Biochemistry. 2004;43:3731-3739.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 45]  [Cited by in RCA: 56]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
95.  Keum YS. Regulation of Nrf2-Mediated Phase II Detoxification and Anti-oxidant Genes. Biomol Ther (Seoul). 2012;20:144-151.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 64]  [Cited by in RCA: 88]  [Article Influence: 8.0]  [Reference Citation Analysis (0)]
96.  Cominacini L, Mozzini C, Garbin U, Pasini A, Stranieri C, Solani E, Vallerio P, Tinelli IA, Fratta Pasini A. Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases. Free Radic Biol Med. 2015;88:233-242.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 119]  [Cited by in RCA: 142]  [Article Influence: 14.2]  [Reference Citation Analysis (0)]
97.  Abdalkader M, Lampinen R, Kanninen KM, Malm TM, Liddell JR. Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration. Front Neurosci. 2018;12:466.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 172]  [Cited by in RCA: 338]  [Article Influence: 48.3]  [Reference Citation Analysis (0)]
98.  Björnsson HK, Björnsson ES. Drug-induced liver injury: Pathogenesis, epidemiology, clinical features, and practical management. Eur J Intern Med. 2022;97:26-31.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 10]  [Cited by in RCA: 79]  [Article Influence: 26.3]  [Reference Citation Analysis (0)]
99.  Rousta AM, Mirahmadi SM, Shahmohammadi A, Mehrabi Z, Fallah S, Baluchnejadmojarad T, Roghani M. Therapeutic Potential of Isorhamnetin following Acetaminophen-Induced Hepatotoxicity through Targeting NLRP3/NF-κB/Nrf2. Drug Res (Stuttg). 2022;72:245-254.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 3]  [Cited by in RCA: 24]  [Article Influence: 8.0]  [Reference Citation Analysis (0)]
100.  Emad D, Bayoumi AMA, Gebril SM, Ali DME, Waz S. Modulation of keap-1/Nrf2/HO-1 and NF-ĸb/caspase-3 signaling pathways by dihydromyricetin ameliorates sodium valproate-induced liver injury. Arch Biochem Biophys. 2024;758:110084.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 5]  [Reference Citation Analysis (0)]
101.  Zhai F, Wang J, Wan X, Liu Y, Mao X. Dual anti-inflammatory effects of curcumin and berberine on acetaminophen-induced liver injury in mice by inhibiting NF-κB activation via PI3K/AKT and PPARγ signaling pathways. Biochem Biophys Res Commun. 2024;734:150772.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 5]  [Reference Citation Analysis (0)]
102.  Jin H, He J, Wu M, Wang X, Jia L, Zhang L, Guo J. Resveratrol Alleviated T-2 Toxin-Induced Liver Injury via Preservation of Nrf2 Pathway and GSH Synthesis. Environ Toxicol. 2025;40:19-29.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 5]  [Reference Citation Analysis (0)]
103.  Gao Y, Chu SF, Zhang Z, Ai QD, Xia CY, Huang HY, Chen NH. Ginsenoside Rg1 prevents acetaminophen-induced oxidative stress and apoptosis via Nrf2/ARE signaling pathway. J Asian Nat Prod Res. 2019;21:782-797.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 11]  [Cited by in RCA: 14]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
104.  Pan CW, Yang SX, Pan ZZ, Zheng B, Wang JZ, Lu GR, Xue ZX, Xu CL. Andrographolide ameliorates d-galactosamine/lipopolysaccharide-induced acute liver injury by activating Nrf2 signaling pathway. Oncotarget. 2017;8:41202-41210.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 45]  [Cited by in RCA: 40]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
105.  Li L, Huang W, Wang S, Sun K, Zhang W, Ding Y, Zhang L, Tumen B, Ji L, Liu C. Astragaloside IV Attenuates Acetaminophen-Induced Liver Injuries in Mice by Activating the Nrf2 Signaling Pathway. Molecules. 2018;23:2032.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 20]  [Cited by in RCA: 44]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
106.  Wu CT, Deng JS, Huang WC, Shieh PC, Chung MI, Huang GJ. Salvianolic Acid C against Acetaminophen-Induced Acute Liver Injury by Attenuating Inflammation, Oxidative Stress, and Apoptosis through Inhibition of the Keap1/Nrf2/HO-1 Signaling. Oxid Med Cell Longev. 2019;2019:9056845.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 49]  [Cited by in RCA: 104]  [Article Influence: 17.3]  [Reference Citation Analysis (0)]
107.  Liu Z, Hou J. Hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection. Int J Med Sci. 2006;3:57-62.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 54]  [Cited by in RCA: 60]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
108.  Saraceni C, Birk J. A Review of Hepatitis B Virus and Hepatitis C Virus Immunopathogenesis. J Clin Transl Hepatol. 2021;9:409-418.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 2]  [Cited by in RCA: 11]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
109.  Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012;24:981-990.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 2639]  [Cited by in RCA: 3074]  [Article Influence: 236.5]  [Reference Citation Analysis (1)]
110.  Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, Weinman SA. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology. 2002;122:366-375.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 690]  [Cited by in RCA: 680]  [Article Influence: 29.6]  [Reference Citation Analysis (0)]
111.  Bender D, Hildt E. Effect of Hepatitis Viruses on the Nrf2/Keap1-Signaling Pathway and Its Impact on Viral Replication and Pathogenesis. Int J Mol Sci. 2019;20:4659.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 20]  [Cited by in RCA: 34]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
112.  Sillanpää M, Melén K, Porkka P, Fagerlund R, Nevalainen K, Lappalainen M, Julkunen I. Hepatitis C virus core, NS3, NS4B and NS5A are the major immunogenic proteins in humoral immunity in chronic HCV infection. Virol J. 2009;6:84.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 30]  [Cited by in RCA: 35]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
113.  Protzer U, Seyfried S, Quasdorff M, Sass G, Svorcova M, Webb D, Bohne F, Hösel M, Schirmacher P, Tiegs G. Antiviral activity and hepatoprotection by heme oxygenase-1 in hepatitis B virus infection. Gastroenterology. 2007;133:1156-1165.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 116]  [Cited by in RCA: 123]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
114.  Zhu Z, Wilson AT, Mathahs MM, Wen F, Brown KE, Luxon BA, Schmidt WN. Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury. Hepatology. 2008;48:1430-1439.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 111]  [Cited by in RCA: 110]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
115.  Lee JC, Tseng CK, Young KC, Sun HY, Wang SW, Chen WC, Lin CK, Wu YH. Andrographolide exerts anti-hepatitis C virus activity by up-regulating haeme oxygenase-1 via the p38 MAPK/Nrf2 pathway in human hepatoma cells. Br J Pharmacol. 2014;171:237-252.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 115]  [Cited by in RCA: 134]  [Article Influence: 12.2]  [Reference Citation Analysis (0)]
116.  Tseng CK, Hsu SP, Lin CK, Wu YH, Lee JC, Young KC. Celastrol inhibits hepatitis C virus replication by upregulating heme oxygenase-1 via the JNK MAPK/Nrf2 pathway in human hepatoma cells. Antiviral Res. 2017;146:191-200.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 29]  [Cited by in RCA: 40]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
117.  Chen WC, Wang SY, Chiu CC, Tseng CK, Lin CK, Wang HC, Lee JC. Lucidone suppresses hepatitis C virus replication by Nrf2-mediated heme oxygenase-1 induction. Antimicrob Agents Chemother. 2013;57:1180-1191.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 49]  [Cited by in RCA: 44]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
118.  Yu JS, Chen WC, Tseng CK, Lin CK, Hsu YC, Chen YH, Lee JC. Sulforaphane Suppresses Hepatitis C Virus Replication by Up-Regulating Heme Oxygenase-1 Expression through PI3K/Nrf2 Pathway. PLoS One. 2016;11:e0152236.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 27]  [Cited by in RCA: 37]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
119.  Chen MH, Lee MY, Chuang JJ, Li YZ, Ning ST, Chen JC, Liu YW. Curcumin inhibits HCV replication by induction of heme oxygenase-1 and suppression of AKT. Int J Mol Med. 2012;30:1021-1028.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 46]  [Cited by in RCA: 53]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
120.  Yang X, Li Q, Liu W, Zong C, Wei L, Shi Y, Han Z. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment. Cell Mol Immunol. 2023;20:583-599.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 15]  [Cited by in RCA: 53]  [Article Influence: 26.5]  [Reference Citation Analysis (0)]
121.  Roehlen N, Crouchet E, Baumert TF. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells. 2020;9:875.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 198]  [Cited by in RCA: 753]  [Article Influence: 150.6]  [Reference Citation Analysis (0)]
122.  Zhang M, Serna-Salas S, Damba T, Borghesan M, Demaria M, Moshage H. Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives. Mech Ageing Dev. 2021;199:111572.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 6]  [Cited by in RCA: 82]  [Article Influence: 20.5]  [Reference Citation Analysis (0)]
123.  Parola M, Pinzani M. Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med. 2019;65:37-55.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 286]  [Cited by in RCA: 784]  [Article Influence: 112.0]  [Reference Citation Analysis (0)]
124.  Gong Y, Yang Y. Activation of Nrf2/AREs-mediated antioxidant signalling, and suppression of profibrotic TGF-β1/Smad3 pathway: a promising therapeutic strategy for hepatic fibrosis - A review. Life Sci. 2020;256:117909.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 23]  [Cited by in RCA: 48]  [Article Influence: 9.6]  [Reference Citation Analysis (0)]
125.  Sass G, Barikbin R, Tiegs G. The multiple functions of heme oxygenase-1 in the liver. Z Gastroenterol. 2012;50:34-40.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 57]  [Cited by in RCA: 64]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
126.  Yang JJ, Tao H, Huang C, Li J. Nuclear erythroid 2-related factor 2: a novel potential therapeutic target for liver fibrosis. Food Chem Toxicol. 2013;59:421-427.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 44]  [Cited by in RCA: 56]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
127.  Macías-Pérez JR, Vázquez-López BJ, Muñoz-Ortega MH, Aldaba-Muruato LR, Martínez-Hernández SL, Sánchez-Alemán E, Ventura-Juárez J. Curcumin and α/β-Adrenergic Antagonists Cotreatment Reverse Liver Cirrhosis in Hamsters: Participation of Nrf-2 and NF-κB. J Immunol Res. 2019;2019:3019794.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 5]  [Cited by in RCA: 12]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
128.  Gowifel AMH, Khalil MG, Nada SA, Kenawy SA, Ahmed KA, Salama MM, Safar MM. Combination of pomegranate extract and curcumin ameliorates thioacetamide-induced liver fibrosis in rats: impact on TGF-β/Smad3 and NF-κB signaling pathways. Toxicol Mech Methods. 2020;30:620-633.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 8]  [Cited by in RCA: 31]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
129.  Zou L, Chen S, Li L, Wu T. The protective effect of hyperoside on carbon tetrachloride-induced chronic liver fibrosis in mice via upregulation of Nrf2. Exp Toxicol Pathol. 2017;69:451-460.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 27]  [Cited by in RCA: 35]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
130.  Chen Q, Zhang H, Cao Y, Li Y, Sun S, Zhang J, Zhang G. Schisandrin B attenuates CCl(4)-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-β/Smad signaling pathways. Drug Des Devel Ther. 2017;11:2179-2191.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 58]  [Cited by in RCA: 87]  [Article Influence: 10.9]  [Reference Citation Analysis (0)]
131.  Wang R, Wang J, Song F, Li S, Yuan Y. Tanshinol ameliorates CCl(4)-induced liver fibrosis in rats through the regulation of Nrf2/HO-1 and NF-κB/IκBα signaling pathway. Drug Des Devel Ther. 2018;12:1281-1292.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 50]  [Cited by in RCA: 66]  [Article Influence: 9.4]  [Reference Citation Analysis (0)]
132.  Li S, Wang R, Song F, Chen P, Gu Y, Chen C, Yuan Y. Salvianolic acid A suppresses CCl(4)-induced liver fibrosis through regulating the Nrf2/HO-1, NF-κB/IκBα, p38 MAPK, and JAK1/STAT3 signaling pathways. Drug Chem Toxicol. 2023;46:304-313.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 6]  [Cited by in RCA: 15]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
133.  Fan J, Chen Q, Wei L, Zhou X, Wang R, Zhang H. Asiatic acid ameliorates CCl(4)-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways. Drug Des Devel Ther. 2018;12:3595-3605.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 24]  [Cited by in RCA: 46]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
134.  Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301-1314.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 2800]  [Cited by in RCA: 4107]  [Article Influence: 586.7]  [Reference Citation Analysis (6)]
135.  Ganesan P, Kulik LM. Hepatocellular Carcinoma: New Developments. Clin Liver Dis. 2023;27:85-102.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 1]  [Cited by in RCA: 234]  [Article Influence: 117.0]  [Reference Citation Analysis (0)]
136.  Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16:589-604.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 2184]  [Cited by in RCA: 2905]  [Article Influence: 484.2]  [Reference Citation Analysis (17)]
137.  Xu D, Xu M, Jeong S, Qian Y, Wu H, Xia Q, Kong X. The Role of Nrf2 in Liver Disease: Novel Molecular Mechanisms and Therapeutic Approaches. Front Pharmacol. 2018;9:1428.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 205]  [Cited by in RCA: 194]  [Article Influence: 32.3]  [Reference Citation Analysis (0)]
138.  Hayes JD, McMahon M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci. 2009;34:176-188.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 647]  [Cited by in RCA: 698]  [Article Influence: 43.6]  [Reference Citation Analysis (0)]
139.  Hallis SP, Kim JM, Kwak MK. Emerging Role of NRF2 Signaling in Cancer Stem Cell Phenotype. Mol Cells. 2023;46:153-164.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 7]  [Cited by in RCA: 15]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
140.  Loboda A, Jozkowicz A, Dulak J. HO-1/CO system in tumor growth, angiogenesis and metabolism - Targeting HO-1 as an anti-tumor therapy. Vascul Pharmacol. 2015;74:11-22.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 113]  [Cited by in RCA: 144]  [Article Influence: 14.4]  [Reference Citation Analysis (0)]
141.  Lohitesh K, Chowdhury R, Mukherjee S. Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight. Cancer Cell Int. 2018;18:44.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 115]  [Cited by in RCA: 197]  [Article Influence: 28.1]  [Reference Citation Analysis (0)]
142.  Jeddi F, Soozangar N, Sadeghi MR, Somi MH, Samadi N. Contradictory roles of Nrf2/Keap1 signaling pathway in cancer prevention/promotion and chemoresistance. DNA Repair (Amst). 2017;54:13-21.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 46]  [Cited by in RCA: 71]  [Article Influence: 8.9]  [Reference Citation Analysis (0)]
143.  Li Y, Deng X, Tan X, Li Q, Yu Z, Wu W, Ma X, Zeng J, Wang X. Protective role of curcumin in disease progression from non-alcoholic fatty liver disease to hepatocellular carcinoma: a meta-analysis. Front Pharmacol. 2024;15:1343193.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 9]  [Reference Citation Analysis (0)]
144.  Moghadam D, Zarei R, Vakili S, Ghojoghi R, Zarezade V, Veisi A, Sabaghan M, Azadbakht O, Behrouj H. The effect of natural polyphenols Resveratrol, Gallic acid, and Kuromanin chloride on human telomerase reverse transcriptase (hTERT) expression in HepG2 hepatocellular carcinoma: role of SIRT1/Nrf2 signaling pathway and oxidative stress. Mol Biol Rep. 2023;50:77-84.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 17]  [Reference Citation Analysis (0)]
145.  Wagner AE, Boesch-Saadatmandi C, Breckwoldt D, Schrader C, Schmelzer C, Döring F, Hashida K, Hori O, Matsugo S, Rimbach G. Ascorbic acid partly antagonizes resveratrol mediated heme oxygenase-1 but not paraoxonase-1 induction in cultured hepatocytes - role of the redox-regulated transcription factor Nrf2. BMC Complement Altern Med. 2011;11:1.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 73]  [Cited by in RCA: 89]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
146.  Sun Y, Yuan X, Zhang F, Han Y, Chang X, Xu X, Li Y, Gao X. Berberine ameliorates fatty acid-induced oxidative stress in human hepatoma cells. Sci Rep. 2017;7:11340.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 31]  [Cited by in RCA: 49]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
147.  Fang M, Huang DR, Zhang JW, Liao WJ, Wu F, Liu YW. [Tanshinone Ⅱ_A exerts anti-hepatocellular carcinoma effects by inhibiting oxidative stress via PI3K/Akt and Nrf2/HO-1 signaling pathway]. Zhongguo Zhong Yao Za Zhi. 2024;49:6724-6734.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 2]  [Reference Citation Analysis (0)]
148.  Zhou H, Liu Y, Su Y, Ji P, Kong L, Sun R, Zhang D, Xu H, Li W, Li W. Ginsenoside Rg1 attenuates lipopolysaccharide-induced chronic liver damage by activating Nrf2 signaling and inhibiting inflammasomes in hepatic cells. J Ethnopharmacol. 2024;324:117794.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 11]  [Reference Citation Analysis (0)]
149.  Liu X, Liu T, Zhou Z, Bian K, Qiu C, Zhang F. Brusatol improves the efficacy of sorafenib in Huh7 cells via ferroptosis resistance dependent Nrf2 signaling pathway. Biochem Biophys Res Commun. 2024;734:150762.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 1]  [Reference Citation Analysis (0)]
150.  Narożna M, Krajka-Kuźniak V, Kleszcz R, Bednarczyk-Cwynar B, Szaefer H, Baer-Dubowska W. Activation of the Nrf2 response by oleanolic acid oxime morpholide (3-hydroxyiminoolean-12-en-28-oic acid morpholide) is associated with its ability to induce apoptosis and inhibit proliferation in HepG2 hepatoma cells. Eur J Pharmacol. 2020;883:173307.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 6]  [Cited by in RCA: 9]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
151.  Hassan HM, Hamdan AM, Alattar A, Alshaman R, Bahattab O, Al-Gayyar MMH. Evaluating anticancer activity of emodin by enhancing antioxidant activities and affecting PKC/ADAMTS4 pathway in thioacetamide-induced hepatocellular carcinoma in rats. Redox Rep. 2024;29:2365590.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in RCA: 7]  [Reference Citation Analysis (0)]
152.  Sun YK, Zhang YF, Xie L, Rong F, Zhu XY, Xie J, Zhou H, Xu T. Progress in the treatment of drug-induced liver injury with natural products. Pharmacol Res. 2022;183:106361.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 1]  [Cited by in RCA: 49]  [Article Influence: 16.3]  [Reference Citation Analysis (0)]
153.  Fu K, Wang C, Ma C, Zhou H, Li Y. The Potential Application of Chinese Medicine in Liver Diseases: A New Opportunity. Front Pharmacol. 2021;12:771459.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 15]  [Cited by in RCA: 26]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
154.  Chopra B, Dhingra AK. Natural products: A lead for drug discovery and development. Phytother Res. 2021;35:4660-4702.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 19]  [Cited by in RCA: 198]  [Article Influence: 49.5]  [Reference Citation Analysis (0)]
155.  Chang R, Chen L, Qamar M, Wen Y, Li L, Zhang J, Li X, Assadpour E, Esatbeyoglu T, Kharazmi MS, Li Y, Jafari SM. The bioavailability, metabolism and microbial modulation of curcumin-loaded nanodelivery systems. Adv Colloid Interface Sci. 2023;318:102933.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 39]  [Reference Citation Analysis (0)]
156.  Yang Y, Sun Y, Gu T, Yan Y, Guo J, Zhang X, Pang H, Chen J. The Metabolic Characteristics and Bioavailability of Resveratrol Based on Metabolic Enzymes. Nutr Rev. 2025;83:749-770.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 1]  [Cited by in RCA: 3]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
157.  Singh K, Gupta JK, Chanchal DK, Shinde MG, Kumar S, Jain D, Almarhoon ZM, Alshahrani AM, Calina D, Sharifi-Rad J, Tripathi A. Natural products as drug leads: exploring their potential in drug discovery and development. Naunyn Schmiedebergs Arch Pharmacol. 2025;398:4673-4687.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 2]  [Cited by in RCA: 6]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
158.  Dinkova-Kostova AT, Copple IM. Advances and challenges in therapeutic targeting of NRF2. Trends Pharmacol Sci. 2023;44:137-149.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 1]  [Cited by in RCA: 121]  [Article Influence: 60.5]  [Reference Citation Analysis (0)]
159.  Moon EJ, Giaccia A. Dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment. Free Radic Biol Med. 2015;79:292-299.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 121]  [Cited by in RCA: 139]  [Article Influence: 13.9]  [Reference Citation Analysis (0)]
160.  Loguercio C, Andreone P, Brisc C, Brisc MC, Bugianesi E, Chiaramonte M, Cursaro C, Danila M, de Sio I, Floreani A, Freni MA, Grieco A, Groppo M, Lazzari R, Lobello S, Lorefice E, Margotti M, Miele L, Milani S, Okolicsanyi L, Palasciano G, Portincasa P, Saltarelli P, Smedile A, Somalvico F, Spadaro A, Sporea I, Sorrentino P, Vecchione R, Tuccillo C, Del Vecchio Blanco C, Federico A. Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic Biol Med. 2012;52:1658-1665.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 201]  [Cited by in RCA: 185]  [Article Influence: 14.2]  [Reference Citation Analysis (0)]
161.  Tang R, Li R, Li H, Ma XL, Du P, Yu XY, Ren L, Wang LL, Zheng WS. Design of Hepatic Targeted Drug Delivery Systems for Natural Products: Insights into Nomenclature Revision of Nonalcoholic Fatty Liver Disease. ACS Nano. 2021;15:17016-17046.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 11]  [Cited by in RCA: 31]  [Article Influence: 7.8]  [Reference Citation Analysis (0)]
162.  Yatoo MI, Gopalakrishnan A, Saxena A, Parray OR, Tufani NA, Chakraborty S, Tiwari R, Dhama K, Iqbal HMN. Anti-Inflammatory Drugs and Herbs with Special Emphasis on Herbal Medicines for Countering Inflammatory Diseases and Disorders - A Review. Recent Pat Inflamm Allergy Drug Discov. 2018;12:39-58.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 148]  [Cited by in RCA: 108]  [Article Influence: 15.4]  [Reference Citation Analysis (0)]
163.  Sailo BL, Chauhan S, Hegde M, Girisa S, Alqahtani MS, Abbas M, Goel A, Sethi G, Kunnumakkara AB. Therapeutic potential of tocotrienols as chemosensitizers in cancer therapy. Phytother Res. 2025;39:1694-1720.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 2]  [Cited by in RCA: 2]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
164.  Manawy SM, Faruk EM, Hindawy RF, Hassan MM, Farrag DMG, Bashar MAE, Fouad H, Bagabir RA, Hassan DAA, Zaazaa AM, Hablas MGA, Kamal KM. Modulation of the Sirtuin-1 signaling pathway in doxorubicin-induced nephrotoxicity (synergistic amelioration by resveratrol and pirfenidone). Tissue Cell. 2024;87:102330.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 4]  [Reference Citation Analysis (0)]
165.  Robledinos-Antón N, Fernández-Ginés R, Manda G, Cuadrado A. Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development. Oxid Med Cell Longev. 2019;2019:9372182.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 252]  [Cited by in RCA: 393]  [Article Influence: 65.5]  [Reference Citation Analysis (0)]
166.  Kundrapu DB, Malla RR. Advances in Quercetin for Drug-Resistant Cancer Therapy: Mechanisms, Applications, and Delivery Systems. Crit Rev Oncog. 2023;28:15-26.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 2]  [Reference Citation Analysis (0)]
167.  Wu H, Zhang L, Dong X, Yang J, Zheng L, Li L, Liu X, Jin M, Zhang P. Targeted delivery of berberine using bionic nanomaterials for Atherosclerosis therapy. Biomed Pharmacother. 2024;178:117135.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 5]  [Reference Citation Analysis (0)]
168.  Wang H, Zheng Y, Sun Q, Zhang Z, Zhao M, Peng C, Shi S. Ginsenosides emerging as both bifunctional drugs and nanocarriers for enhanced antitumor therapies. J Nanobiotechnology. 2021;19:322.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 47]  [Cited by in RCA: 56]  [Article Influence: 14.0]  [Reference Citation Analysis (0)]
169.  Machado IF, Miranda RG, Dorta DJ, Rolo AP, Palmeira CM. Targeting Oxidative Stress with Polyphenols to Fight Liver Diseases. Antioxidants (Basel). 2023;12:1212.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 33]  [Reference Citation Analysis (0)]
170.  Yuan J, Mesenbrink P, Zhou J, Liu J, Zhu R, Koch G. Clinical Study Design to Assess Both Short- and Long-term Efficacy in Addition to Group Sequential Test on Safety. Ther Innov Regul Sci. 2018;52:690-695.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 1]  [Reference Citation Analysis (0)]
171.  Syed AM, Ram C, Murty US, Sahu BD. A review on herbal Nrf2 activators with preclinical evidence in cardiovascular diseases. Phytother Res. 2021;35:5068-5102.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 7]  [Cited by in RCA: 17]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
172.  Qin S, Chen Z, Wen Y, Yi Y, Lv C, Zeng C, Chen L, Shi M. Phytochemical activators of Nrf2: a review of therapeutic strategies in diabetes. Acta Biochim Biophys Sin (Shanghai). 2022;55:11-22.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 4]  [Reference Citation Analysis (0)]
173.  Görg B, Karababa A, Häussinger D. Hepatic Encephalopathy and Astrocyte Senescence. J Clin Exp Hepatol. 2018;8:294-300.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 29]  [Cited by in RCA: 47]  [Article Influence: 6.7]  [Reference Citation Analysis (0)]
174.  López-Franco Ó, Morin JP, Cortés-Sol A, Molina-Jiménez T, Del Moral DI, Flores-Muñoz M, Roldán-Roldán G, Juárez-Portilla C, Zepeda RC. Cognitive Impairment After Resolution of Hepatic Encephalopathy: A Systematic Review and Meta-Analysis. Front Neurosci. 2021;15:579263.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 6]  [Cited by in RCA: 19]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
175.  Gautam S, Jain A, Chaudhary J, Gautam M, Gaur M, Grover S. Concept of mental health and mental well-being, it's determinants and coping strategies. Indian J Psychiatry. 2024;66:S231-S244.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 32]  [Reference Citation Analysis (0)]
176.  Aldridge DR, Tranah EJ, Shawcross DL. Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation. J Clin Exp Hepatol. 2015;5:S7-S20.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 194]  [Cited by in RCA: 221]  [Article Influence: 22.1]  [Reference Citation Analysis (0)]
177.  Cardenas-Iniguez C, Burnor E, Herting MM. Neurotoxicants, the Developing Brain, and Mental Health. Biol Psychiatry Glob Open Sci. 2022;2:223-232.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 17]  [Cited by in RCA: 21]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
178.  Khalil HMA, Khalil IA, Al-Mokaddem AK, Hassan M, El-Shiekh RA, Eliwa HA, Tawfek AM, El-Maadawy WH. Ashwagandha-loaded nanocapsules improved the behavioral alterations, and blocked MAPK and induced Nrf2 signaling pathways in a hepatic encephalopathy rat model. Drug Deliv Transl Res. 2023;13:252-274.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 12]  [Reference Citation Analysis (0)]
179.  Amirshahrokhi K, Niapour A. Carvedilol attenuates brain damage in mice with hepatic encephalopathy. Int Immunopharmacol. 2022;111:109119.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 14]  [Reference Citation Analysis (0)]
180.  Jin X, Chen D, Wu F, Zhang L, Huang Y, Lin Z, Wang X, Wang R, Xu L, Chen Y. Hydrogen Sulfide Protects Against Ammonia-Induced Neurotoxicity Through Activation of Nrf2/ARE Signaling in Astrocytic Model of Hepatic Encephalopathy. Front Cell Neurosci. 2020;14:573422.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in Crossref: 8]  [Cited by in RCA: 17]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
181.  Bellaver B, Souza DG, Souza DO, Quincozes-Santos A. Hippocampal Astrocyte Cultures from Adult and Aged Rats Reproduce Changes in Glial Functionality Observed in the Aging Brain. Mol Neurobiol. 2017;54:2969-2985.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 89]  [Cited by in RCA: 100]  [Article Influence: 12.5]  [Reference Citation Analysis (0)]
182.  Zhao P, Wei Y, Sun G, Xu L, Wang T, Tian Y, Chao H, Tu Y, Ji J. Fetuin-A alleviates neuroinflammation against traumatic brain injury-induced microglial necroptosis by regulating Nrf-2/HO-1 pathway. J Neuroinflammation. 2022;19:269.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Full Text (PDF)]  [Cited by in RCA: 50]  [Reference Citation Analysis (0)]
183.  Gao Y, Zhang H, Wang J, Li F, Li X, Li T, Wang C, Li L, Peng R, Liu L, Cui W, Zhang S, Zhang J. Annexin A5 ameliorates traumatic brain injury-induced neuroinflammation and neuronal ferroptosis by modulating the NF-ĸB/HMGB1 and Nrf2/HO-1 pathways. Int Immunopharmacol. 2023;114:109619.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 40]  [Reference Citation Analysis (0)]
184.  Görg B, Karababa A, Schütz E, Paluschinski M, Schrimpf A, Shafigullina A, Castoldi M, Bidmon HJ, Häussinger D. O-GlcNAcylation-dependent upregulation of HO1 triggers ammonia-induced oxidative stress and senescence in hepatic encephalopathy. J Hepatol. 2019;71:930-941.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 29]  [Cited by in RCA: 51]  [Article Influence: 8.5]  [Reference Citation Analysis (0)]
185.  Navarro E, Esteras N. Multitarget Effects of Nrf2 Signalling in the Brain: Common and Specific Functions in Different Cell Types. Antioxidants (Basel). 2024;13:1502.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in RCA: 4]  [Reference Citation Analysis (0)]
186.  Wang Y, Xia H, Yu X, Lu T, Chi X, Cai J. Hemin protects against hippocampal damage following orthotopic autologous liver transplantation in adult rats. Life Sci. 2015;135:27-34.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 4]  [Cited by in RCA: 6]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
187.  Khalil HMA, Eliwa HA, El-Shiekh RA, Al-Mokaddem AK, Hassan M, Tawfek AM, El-Maadawy WH. Ashwagandha (Withania somnifera) root extract attenuates hepatic and cognitive deficits in thioacetamide-induced rat model of hepatic encephalopathy via induction of Nrf2/HO-1 and mitigation of NF-κB/MAPK signaling pathways. J Ethnopharmacol. 2021;277:114141.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 33]  [Cited by in RCA: 55]  [Article Influence: 13.8]  [Reference Citation Analysis (0)]
188.  Ramos-Tovar E, Flores-Beltrán RE, Galindo-Gómez S, Vera-Aguilar E, Diaz-Ruiz A, Montes S, Camacho J, Tsutsumi V, Muriel P. Stevia rebaudiana tea prevents experimental cirrhosis via regulation of NF-κB, Nrf2, transforming growth factor beta, Smad7, and hepatic stellate cell activation. Phytother Res. 2018;32:2568-2576.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 15]  [Cited by in RCA: 22]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
189.  Baraka SM, Saleh DO, Ghaly NS, Melek FR, Gamal El Din AA, Khalil WKB, Said MM, Medhat AM. Flavonoids from Barnebydendron riedelii leaf extract mitigate thioacetamide-induced hepatic encephalopathy in rats: The interplay of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways. Bioorg Chem. 2020;105:104444.  [RCA]  [PubMed]  [DOI]  [Full Text]  [Cited by in Crossref: 13]  [Cited by in RCA: 24]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]