In acute myeloid leukemia (AML), high expression of BRD4 is associated with poor prognosis. BET inhibitors that mainly inhibit BRD4 can induce AML cell death, but some AML cells are insensitive to BET inhibitors. We found that BET inhibitors could promote the up-regulation of the ferroptosis signaling pathway in AML. In this study, we intend to investigate the synergistic effects of BET inhibitors with ferroptosis inducers in AML cells. The combination of BET inhibitors with ferroptosis inducers (RSL3, FIN56, and Erastin) markedly reduced AML cell viability and increased cell death, as demonstrated by CCK-8 assays and flow cytometry analysis across multiple AML cell lines and primary AML patient samples. Moreover, BET inhibitors combined with ferroptosis inducers elevated the lipid reactive oxygen species (ROS) levels, indicating heightened lipid peroxidation, a hallmark of ferroptosis. Mechanistically, BET inhibitor and ferroptosis inducer co-targeted the BRD4/c-Myc/NRF2 axis, leading to downregulation of NRF2, key regulators of AML cell survival and oxidative stress resistance. NRF2 knockdown amplified the anti-AML effect of this combined treatment, whereas NRF2 overexpression negated this synergy, highlighting its critical role in mediating ferroptosis resistance. Finally, survival analyses of AML patients from the TCGA and GSE71014 datasets revealed that elevated expression of BRD4, NRF2, and its downstream target GPX4, an essential ferroptosis regulator, correlated with poor overall survival, highlighting the clinical relevance of our findings. In all, combining BET inhibition with ferroptosis induction could enhance anti-leukemia effect and represent a novel therapeutic strategy for targeting AML cells.

Atherosclerosis (AS) is a chronic inflammatory disease caused by oxidative stress and the oxidation of low‑density lipoprotein (LDL). Xylitol, a widely used sugar substitute, has antioxidant potential; however, its effects on LDL‑induced oxidative stress in AS remain unclear. Using western blot, reverse transcription‑quantitative PCR, flow cytometry and so on, the present study investigated the role of xylitol in mitigating oxidative stress induced by high levels of LDL in Tohoku Hospital Pediatrics‑1 (THP‑1) human monocytic cell line), a model for studying AS. Xylitol significantly alleviated high LDL‑induced oxidative stress in THP‑1 cells and decreased reactive oxygen species levels, malondialdehyde content and the expression of NADPH oxidase family enzymes. Concurrently, xylitol enhanced the activity and expression of superoxide dismutase and increased the glutathione levels. Mechanistically, xylitol activated the nuclear factor erythroid 2‑related factor 2 (Nrf2)/heme oxygenase‑1 (HO‑1) axis by increasing the NADPH/NADP+ ratio via the regulation of the pentose phosphate pathway via the Nrf2 transcription factor. This led to a decrease in LDL oxidative modification in THP‑1 cells (Figs. 6,7). Overall, xylitol attenuates high LDL level‑induced oxidative stress in THP‑1 cells by modulating the Nrf2‑mediated pentose phosphate pathway and activating the Nrf2/HO‑1 axis, highlighting its potential for the prevention and treatment of AS.

To investigate the therapeutic potential and renal protective mechanisms of hirsutine in diabetic kidney disease (DKD).

A DKD model was induced in Sprague-Dawley rats using a high-fat diet (HFD) and streptozotocin (STZ). High glucose (HG)-stimulated HK-2 cells served as an in vitro model. Reactive oxygen species (ROS) levels in kidney tissues were measured using dihydroethidium (DHE) staining. ELISA was performed to measure MDA, SOD, and GSH in both rat tissues and HK-2 cells. Western blot and immunofluorescence analyses evaluated renal fibrosis, the Nrf2 signaling pathway, and autophagy-related proteins (Beclin 1, LC3I/II, P62).

Hirsutine treatment significantly improved metabolic and renal parameters in rats, enhancing renal function and reducing fibrosis, as shown by lower levels of Vimentin, Collagen-IV, and α-SMA. It alleviated oxidative stress, indicated by reduced ROS and MDA levels and increased SOD and GSH activity. Additionally, hirsutine enhanced autophagy, reflected by higher Beclin 1 and LC3I/II levels and decreased P62 expression. By disrupting the Keap1-Nrf2 interaction, hirsutine increased Nrf2 levels and upregulated antioxidative enzymes like NQO1, SOD-2, and HO-1.

Hirsutine exhibited renoprotective effects in DKD by modulating the Keap1/Nrf2 pathway, mitigating oxidative stress and promoting autophagy, making it a promising candidate for treatment.

Ferroptosis, a newly discovered mode of cell death, is a type of iron-dependent regulated cell death characterized by intracellular excessive lipid peroxidation and imbalanced redox. As the liver is susceptible to oxidative damage and the abnormal iron accumulation is a major feature of most liver diseases, studies on ferroptosis in the field of liver diseases are of great interest. Studies show that targeting the key regulators of ferroptosis can effectively alleviate or even reverse the deterioration process of liver diseases. System Xc- and glutathione peroxidase 4 are the main defense regulators of ferroptosis, while acyl-CoA synthetase long chain family member 4 is a key enzyme causing peroxidation in ferroptosis. Generally speaking, ferroptosis should be suppressed in alcoholic liver disease, non-alcoholic fatty liver disease, and drug-induced liver injury, while it should be induced in liver fibrosis and hepatocellular carcinoma. In this review, we summarize the main regulators involved in ferroptosis and then the mechanisms of ferroptosis in different liver diseases. Treatment options of drugs targeting ferroptosis are further concluded. Determining different triggers of ferroptosis can clarify the mechanism of ferroptosis occurs at both physiological and pathological levels.

The present study was designed to explore the protective effects of artemisinin on alcohol-induced cardiac injuries and its mechanisms. In H9c2 cells, cell viability, reactive oxygen species (ROS), labile iron pool (LIP), and mitochondrial membrane potential (MMP) were measured. In the mouse model of alcohol-induced cardiomyopathy, body weight and electrocardiogram (ECG) were recorded every day. Heart tissue creatine kinase (CK), lactic dehydrogenase (LDH), iron, glutathione (GSH), malondialdehyde (MDA), and histological examination were measured. Western blot assay was performed to evaluate the expression of ferroptosis-related proteins in vitro and in vivo. The results in vitro showed that cell viability was increased, ROS and LIP contents were decreased, and the level of MMP was increased in artemisinin-treated H9c2 cells. Tissues CK, LDH, and GSH were improved after being treated with artemisinin. The ferroptosis biomarkers, including MDA and tissue iron, were attenuated after artemisinin treatment. Artemisinin protected the heart from alcohol damage by ECG and histological examination. Additionally, artemisinin down-regulated the expression of TfR and P53 and up-regulated Nrf2, HO-1, NQO1, and GPX4 expressions in vitro and in vivo. The results showed that both Fer-1 and artemisinin abolished ferroptosis. The data presented here showed that artemisinin had the potential to protect alcohol-induced cardiotoxicity through the inhibition of Nrf2/NQO1-dependent ferroptosis.

The ameliorative effect of traditional Chinese medicine (TCM) on hepatic fibrosis has been widely recognized and researched, but studies on the mechanism of action have been hampered by its complex composition, which requires more in-depth studies to elucidate why and how TCM works. The theory of TCM believes that the liver is closely related to blood circulation, and hepatic fibrosis is caused by blood stagnation. Taohong Siwu Decoction (THSW) is a classic formula for nourishing and invigorating blood and has been used clinically for centuries. Current evidence has demonstrated its ameliorative effect on hepatic fibrosis, but the exact mechanism of action remains unclear.

Exploring the possible mechanism of the anti-hepatic fibrosis effect of THSW by proteomics and validating with in vivo and in vitro studies.

The carbon tetrachloride (CCl4)-induced fibrosis model was conducted in mice and treated with THSW in vivo with colchicine as the positive control. Then serum biomarker alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histopathological analysis were evaluated to examine the effects of THSW. And hepatic fibrosis indicators alpha-smooth muscle actin (α-SMA) and Collagen Ⅰ (Col-Ⅰ) were detected by western blotting, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Additionally, the 4D Label-free quantitative proteomic analysis of liver samples was applied. In vitro, erastin-induced BRL-3A cells, a rat hepatocyte line, were performed as a hepatocyte ferroptosis model and treated with or without drug-containing serum of THSW. Finally, molecular docking was used to verify the binding ability of the main components of THSW to potential targets.

THSW treatment significantly ameliorated serum ALT, AST, hydroxyproline (Hyp) content, α-SMA and Col-Ⅰ mRNA expression in fibrosis mice. Further results showed that THSW decreased the malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE) content and increased the glutathione (GSH) content of liver tissue. Notably, proteomic analyses have identified 294 differentially expressed proteins in the THSW-treated group compared to the model group, with 97 proteins up-regulated and 197 down-regulated. Functional analysis of these differential proteins highlights the significant roles of inflammation and oxidative stress. Further validation in vivo and in vitro, THSW significantly improved the protein expression of glutathione S-transferase M1 (GSTM1), down-regulate the expression of transferrin receptor (TFRC), and kelch-like ECH-associated protein 1(Keap1) proteins, and promote the metabolism of GSH. Especially it reduced serum iron levels, increased total iron binding capacity, and up-regulated recombinant solute carrier family 7, member 11 (SLC7A11), nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPX4) protein expression, suggesting the inhibition of hepatocyte ferroptosis. In addition, the molecular docking results showed that its main components, amygdalin, hydroxysafflor yellow A, paeoniflorin, and albiflorin, possessed good binding ability with Keap1.

THSW represents a novel therapeutic effect on hepatic fibrosis in mice, accompanied by inhibiting hepatocyte ferroptosis. Mechanically, THSW may regulate the glutathione metabolic pathway and TFRC expression through its main ingredients, such as amygdalin, hydroxysafflor yellow A, paeoniflorin, and albiflorin, thereby inhibiting hepatocyte ferroptosis.

Intestinal ischemia/reperfusion (IIR) is a substantial cause of mortality and morbidity worldwide. Octreotide (OCT) has been proven to be effective against various organ insults. However, the exact mechanism by which it exerts protective effect against IIR is still obscure. Thus, the aim was to unveil the potential role of octreotide in an IIR model and decipher its mechanism of action. The rats were allocated into sham-operated, IIR, and OCT groups. Histopathological changes were performed to assess the intestinal injury. Immunohistochemical analysis was used to estimate the NF-κB, Bcl2, caspase-3, IL-17, LC3B, and beclin-1. The mRNA of TNF-α and IL-17 were examined using real time PCR. The levels of p-Nrf2, PRX2, p-JNK, ASK1, and LC3 were assessed using western blot technique. The levels of total antioxidant capacity and SOD were measured using appropriate kits. Furthermore, the protein expressions of Bax, caspase-3, ASK1, and Nrf2 were assessed using proper ELISA kits. Additionally, the comet assay was determined to investigate the effect on apoptosis. At the molecular level, OCT administration upregulated TAC and SOD levels, demonstrating its antioxidant effect. The anti-apoptotic effect was signified by the upregulation of Bcl2 and downregulation of Bax and caspase-3, which was confirmed by comet assay. Furthermore, OCT decreased the levels of TNF-α, NF-κB, and IL-17, confirming its anti-inflammatory effect. OCT pre-treatment triggered autophagy, as evidenced by the upregulation of beclin-1 and LC3B. These effects were accomplished by increasing p-Nrf2 and PRX2 and decreasing ASK1 and p-JNK. Consequently, this impeded the necrosis of intestinal cells and improved the intestinal histoarchitecture abnormalities. Ultimately, OCT successfully ameliorated IIR injury via modulating the Nrf2/PRX2/ASK1/JNK signaling trajectory, leading to autophagic, antioxidant, anti-apoptotic, and anti-inflammatory effects.

Acute liver injury is caused by various reasons and results in abnormal liver function, serving as the basis for various liver diseases. However, there has not been much progress in research on the prevention and treatment of acute liver injury, and drugs directly or specifically used for acute liver injury are still lacking. Recent studies have shown that several types of cell death are closely associated with the onset, progression, and prognosis of liver injury.

In this study, we identified a small molecule compound, GNF-5837, which attenuates the severity of acute liver injury by inhibiting apoptosis, pyroptosis, and ferroptosis. Mechanically, we found that GNF-5837 reduces the generation of reactive oxygen species (ROS) and alleviates oxidative stress by capturing excessive oxidative free radicals generated during cell death, which effectively inhibits apoptosis, pyroptosis, and ferroptosis. The results of animal experiments showed that GNF-5837 can effectively alleviate Con A-induced acute liver injury in vivo by blocking multiple modes of cell death.

Therefore, our research indicates that the small molecule compound GNF-5837 is an oxygen radical scavenger with significant peroxide removal effects, which offer a potential therapeutic approach for cell death caused by imbalances in intracellular oxidative stress levels and provides new insights into the study of acute liver injury.

Globally, drug-induced hepatotoxicity or drug-induced liver injury (DILI) is a serious clinical concern. Knowing the processes and patterns of cell death is essential for finding new therapeutic targets since there are not many alternatives to therapy for severe liver lesions. Excessive lipid peroxidation is a hallmark of ferroptosis, an iron-reliant non-apoptotic cell death linked to various liver pathologies. When iron is pathogenic, concomitant inflammation may exacerbate iron-mediated liver injury, and the hepatocyte necrosis that results is a key element in the fibrogenic response. The idea that dysregulated metabolic pathways and compromised iron homeostasis contribute to the development of liver injury by ferroptosis is being supported by new data. Various ferroptosis-linked genes and pathways have been linked to liver injury, although the molecular processes behind ferroptosis's pathogenicity are not well known. Here, we delve into the features of ferroptosis, the processes governing ferroptosis, and our current knowledge of iron metabolism. We also provide an overview of ferroptosis's involvement in the pathophysiology of liver injury, particularly DILI. Lastly, the therapeutic possibilities of ferroptosis targeting for liver injury management have been provided. Natural products, nanoparticles (NPs), mesenchymal stem cell (MSC), and their exosomes have attracted increasing attention among such therapeutics.

Renal fibrosis is a common pathological process of progressive chronic kidney disease (CKD). However, effective therapy is constrained currently. Autophagy is an important mechanism in kidney injury and repairment but its exact role in renal fibrosis was discrepant according to previous studies. Sulforaphane (SFN), a natural plant compound, has been explored as a promising nutritional therapy for a variety of diseases. But the salutary effect and underlying mechanism of SFN on CKD have not been fully elucidated. In this study, we investigated the effect of SFN on renal fibrosis in unilateral ureteral obstruction (UUO) mice. Then we examined the regulatory effect of SFN on autophagy-related proteins in renal fibroblasts and renal tubular epithelial cells. Our results showed that sulforaphane could significantly alleviate renal fibrosis in UUO mice. In vitro, the expression levels of autophagy-related protein showed that SFN could upregulate the autophagy activity of renal interstitial fibroblasts and downregulate the autophagy activity of renal tubular epithelial cells. Furthermore, we found that phosphorylated mTOR protein levels was reduced in renal fibroblasts and increased in renal tubular epithelial cells after SFN treatment. Our results strongly suggested that SFN could alleviate renal fibrosis through dual regulation of mTOR-mediated autophagy pathway. This finding may provide a new perspective on the renal salutary effect of SFN and provide a preclinical rationale for exploring the therapeutic potential of SFN to slow down renal fibrosis.

Ferroptosis is a mode of programmed cell death that plays an important role in an increasing number of diseases. Recently, ferroptosis was found to be involved in the pathology of acute pancreatitis (AP). We determined that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the ferroptosis process in AP. By inhibiting Nrf2 expression, the death of acinar cells in AP can be increased. Therefore, to help treat AP to a certain extent, we analyzed the effects of astaxanthin and found that it can activate Nrf2 and reduce the pathological process of AP. The activation of Nrf2 improves defective autophagy in AP and inhibits ferroptosis in acinar cells. Specifically, Nrf2 can promote the expression of Gpx4 and ferritin, and can inhibit the formation of Beclin-Slc7a11 complex by improving autophagy, thereby increasing the membrane expression of Slc7a11. Slc7a11/Gpx4 is an important anti-ferroptosis pathway; Slc7a11 can promote the synthesis of glutathione, while Gpx4 can utilize glutathione to exert antioxidative effects. Thus, we demonstrated that Nrf2 activation not only ameliorated defective autophagy at the time of AP but also promoted membrane expression of Slc7a11 to inhibit ferroptosis in acinar cells, thereby alleviating AP.

Mitochondria are metabolic hubs that govern skeletal muscle health. Although exercise has been established as a powerful inducer of quality control processes that ultimately enhance mitochondrial function, there are currently limited pharmaceutical interventions available that emulate exercise-induced mitochondrial adaptations. To investigate a novel candidate for this role, we examined sulforaphane (SFN), a naturally occurring compound found in cruciferous vegetables. SFN has been documented as a potent antioxidant inducer through its activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response pathway. However, its effects on muscle health have been underexplored. To investigate the interplay between chronic exercise and SFN, C2C12 myotubes were electrically stimulated to model chronic contractile activity (CCA) in the presence or absence of SFN. SFN promoted Nrf-2 nuclear translocation, enhanced mitochondrial respiration, and upregulated key antioxidant proteins including catalase and glutathione reductase. These adaptations were accompanied by reductions in cellular and mitochondrial reactive oxygen species (ROS) emission. Signaling toward biogenesis was enhanced, demonstrated by increases in mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α nuclear translocation, PGC-1α promoter activity, mitochondrial content, and organelle branching, suggestive of a larger, more interconnected mitochondrial pool. These mitochondrial adaptations were accompanied by an increase in lysosomal proteins, suggesting coordinated regulation. There was no difference in mitochondrial and antioxidant-related proteins between CCA and non-CCA SFN-treated cells. Our data suggest that SFN activates signaling cascades that are common to those produced by contractile activity, indicating that SFN-centered therapeutic strategies may improve the mitochondrial phenotype in skeletal muscle.NEW & NOTEWORTHY Nrf-2 is a transcription factor that has been implicated in mitigating oxidative stress and regulating mitochondrial homeostasis. However, limited research has demonstrated how Nrf-2-mediated adaptations compare with those produced by exercise. To investigate this, we treated myotubes with Sulforaphane, a well-established Nrf-2 activator, and combined this with stimulation-induced chronic contractile activity to model exercise training. Our work is the first to establish that sulforaphane mimics training-induced mitochondrial adaptations, including enhancements in respiration, biogenesis, and dynamics.

Sepsis-induced acute lung injury (ALI) is a life-threatening condition associated with high morbidity and mortality rates in intensive care units (ICUs). Emerging evidence from clinical studies suggests that compounds derived from traditional Chinese medicine (TCM) have shown promising therapeutic effects in treating sepsis-induced ALI. Hyperoside is a bioactive compound extracted from TCM. Prior studies reported that hyperoside exhibits potent anti-inflammatory, antioxidant, and organ-protective properties, however, the underlying mechanisms of its effects on ALI remain unclear. Hyperoside pretreatment significantly reduced inflammation, iron accumulation, and lipid peroxidation in the pulmonary tissues of ALI mice induced by CLP and in LPS-stimulated MLE-12 cells. In particular, hyperoside preferentially binds with Keap1 at Arg380 and Arg415, thereby inhibiting the ubiquitin-mediated degradation of nuclear Nrf2, promoting its translocation to the nucleus, and leading to upregulation of anti-ferroptosis gene expression. Moreover, the protective effects of hyperoside were significantly abrogated after Nrf2 expression was silenced or its activity was inhibited by chemical inhibitors, highlighting that Nrf2 is critically involved in the impact of hyperoside. This study confirms that hyperoside exhibits a therapeutically protective effect against sepsis-induced ALI by inhibiting ferroptosis through Nrf2-mediated signaling pathway. Hyperoside acts as an Nrf2 activator by preferentially binding to Arg380 and Arg415 of Keap1 and disrupting the Keap1/Nrf2 interaction.

Chronic kidney disease (CKD) is a global health concern caused by conditions such as hypertension, diabetes, hyperlipidemia, and chronic nephritis, leading to structural and functional kidney injury. Kidney fibrosis is a common outcome of CKD progression, with abnormal fatty acid oxidation (FAO) disrupting renal energy homeostasis and leading to functional impairments. This results in maladaptive repair mechanisms and the secretion of profibrotic factors, and exacerbates renal fibrosis. Understanding the molecular mechanisms of renal fibrosis is crucial for delaying CKD progression. Ferroptosis is a type of discovered an iron-dependent lipid peroxidation-regulated cell death. Notably, Ferroptosis contributes to tissue and organ fibrosis, which is correlated with the degree of renal fibrosis. This study aims to clarify the complex mechanisms of ferroptosis in renal parenchymal cells and explore how ferroptosis intervention may help alleviate renal fibrosis, particularly by addressing the gap in CKD mechanisms related to abnormal lipid metabolism under the ferroptosis context. The goal is to provide a new theoretical basis for clinically delaying CKD progression.

Doxorubicin (DOX), an anticancer drug, is used to treat several types of tumors, but it has detrimental side effects that restrict its therapeutic efficacy. One is the iron-dependent form of ferroptosis, which is characterized by elevated ROS production and iron overload. Syzygium aromaticum has a diverse range of biological and pharmaceutical actions due to their antioxidant properties. This study investigated the effect of S. aromaticum extract (SAE) on hepatotoxicity caused by DOX in rats. Phytochemical analysis was performed to assess compounds in SAE. The ADMETlab 2.0 web server was used to predict the pharmacokinetic properties of the most active components of SAE when DOX was injected into rats. Molecular docking studies were performed using AutoDock Vina. Forty male Sprague Dawley rats were divided into four groups of ten rats each (G1 was a negative control group, G2 was given 1/10 of SAE LD50 by oral gavage (340 mg/kg), G3 was given 4 mg/kg of DOX intraperitoneally (i.p.) once a week for a month, and G4 was administered DOX as in G3 and SAE as in G2). After a month, biochemical and histopathological investigations were performed. Rats given SAE had promising levels of phytochemicals, which could significantly ameliorate DOX-induced hepatotoxicity by restoring biochemical alterations, mitigating ferroptosis, and upregulating the NRF-2-SLC7A-11-GPX-4 signaling pathway. These findings suggest that SAE could potentially alleviate DOX-induced hepatotoxicity in rats.

Hepatocellular carcinoma (HCC) is a prevalent and lethal malignancy with significant global impact, necessitating the development of novel therapeutic strategies and drugs. Ferroptosis, a newly identified form of iron-dependent programmed cell death, has emerged as a promising strategy to combat HCC. Sappanone A, an isoflavone compound derived from the heartwood of Biancaea sappan (L.) Tod., is known for its anti-inflammatory and antioxidant properties. However, its anti-HCC effects and underlying mechanisms remain unclear. This study is the first time to demonstrate the anti-tumor effect of Sappanone A on HCC both in vitro and in vivo, through the assessment of cell viability and apoptosis following Sappanone A treatment. Flow cytometry and confocal microscopy revealed that Sappanone A induced ferroptosis in HCC cells by increasing Fe2+ accumulation, reactive oxygen (ROS) level, and lipid peroxidation, specifically targeting inosine monophosphate dehydrogenase-2 (IMPDH2). Additionally, Western blot analysis suggested that the anti-HCC effects of Sappanone A were mediated through the regulation of the NRF2/xCT/GPX4 axis, highlighting its potential to enhance ferroptosis in HCC cells and underscoring the critical role of IMPDH2 in HCC treatment.

Heart failure is primarily characterized by damage to the structure and function of the heart. Ferroptosis represents a form of programmed cell death, and studies indicate that it constitutes one of the primary mechanisms underlying cardiomyocyte death in heart failure. Calycosin, a natural compound derived from astragalus, exhibits various pharmacological properties, including anti-ferroptosis, antioxidant effects, and cardiovascular protection. Nonetheless, the specific role of Calycosin in the treatment of ferroptosis in heart failure remains poorly understood.

This study aims to elucidate the regulatory effect of Calycosin on ferroptosis and its influence on the treatment mechanisms of heart failure through in vivo and in vitro experiments.

A rat model of heart failure was induced using doxorubicin, and the cardiac function was evaluated through cardiac ultrasound examination and NT-Pro BNP detection. Myocardial injury was assessed using H&E staining and Masson staining. The extent of mitochondrial damage was evaluated through transmission electron microscopy. Concurrently, the level of ferroptosis was analyzed by measuring ferroptosis markers, including MDA, ferrous ions, the GSH/GSSG ratio, and GPX4 activity. Subsequently, the molecular mechanism by which Calycosin exerts its therapeutic effects in heart failure was investigated through immunofluorescence and Western blotting. Finally, H9c2 cardiomyocytes were treated with doxorubicin to simulate myocardial injury, and the mechanism by which Calycosin mediates its effects in the treatment of heart failure was further verified through Nrf2 gene silencing.

Calycosin significantly improves cardiac function in rats, reduces serum NT-Pro BNP levels, and alleviates myocardial cell damage. Additionally, it significantly decreases the levels of ferroptosis in myocardial tissue, as confirmed through transmission electron microscopy and the assessment of ferroptosis markers, including MDA, ferrous ions, GSH, and GPX4 activity. At the molecular level, Calycosin exerts its effects by activating the Nrf2/SLC7A11/GPX4 signaling pathway, evidenced by the upregulation of Nrf2, SLC7A11, GPX4, GSS, and GCL protein expression. This process substantially enhances the antioxidant capacity of rat myocardial tissue and effectively suppresses ferroptosis in myocardial cells. The results obtained from both in vivo and in vitro experiments are consistent. Notably, when Nrf2 is silenced, the protective effect of Calycosin on the myocardium is markedly diminished.

Calycosin effectively treats doxorubicin-induced cardiac injury, and its therapeutic effect is likely closely associated with the activation of the Nrf2/SLC7A11/GPX4 signaling pathway and the inhibition of ferroptosis in myocardial cells. Consequently, Calycosin, as a promising compound against doxorubicin-induced cardiotoxicity, warrants further investigation.

Doxorubicin-induced cardiotoxicity (DIC) poses a significant challenge, impeding its widespread application. Emerging evidence suggests the involvement of ferroptosis in the DIC. While the downregulation of SLC7A11 expression has been linked to the promotion of ferroptosis, the precise regulatory mechanism remains unclear. Recent studies, including our own, have highlighted abnormal levels of autophagy adapter protein P62 and autophagy in DIC development. Thus, our study aimed to further investigate the role of autophagy and ferroptosis in DIC, elucidating underlying molecular mechanisms across molecular, cellular, and whole-organ levels utilizing gene knockdown, immunoprecipitation, and mass spectrometry techniques. The results of our findings unveiled cardiomyocyte damage, heightened autophagy levels, and ferroptosis in DOX-treated mouse hearts. Notably, inhibition of autophagy levels attenuated DOX-induced ferroptosis. Mechanistically, we discovered that the autophagy adaptor protein P62 mediates the entry of SLC7A11 into the autophagic pathway for degradation. Furthermore, the addition of autophagy inhibitors (CQ or BAF) could elevate SLC7A11 and GPX4 protein expression, reduce the accumulation of Fe2+ and ROS in cardiomyocytes, and thus mitigate DOX-induced ferroptosis. In summary, our findings underscore the pivotal role of the P62-autophagy pathway in SLC7A11 degradation, modulating ferroptosis to exacerbate DIC. This finding offers significant insights into the underlying molecular mechanisms of DOX-induced ferroptosis and identifies new targets for reversing DIC.

Induction of autophagy represents an effective survival strategy for nutrient-deprived or stressed cancer cells. Autophagy contributes to the modulation of communication within the tumor microenvironment. Here, we conducted a study of the metabolic and signaling implications associated with autophagy induced by glutamine (Gln) and serum starvation and PI3K/mTOR inhibitor and autophagy inducer NVP-BEZ235 (BEZ) in the head and neck squamous cell carcinoma (HNSCC) cell line FaDu. We compared the effect of these different types of autophagy induction on ATP production, lipid peroxidation, mitophagy, RNA cargo of extracellular vesicles (EVs), and EVs-associated cytokine secretome of cancer cells. Both BEZ and starvation resulted in a decline in ATP production. Simultaneously, Gln starvation enhanced oxidative damage of cancer cells by lipid peroxidation. In starved cells, there was a discernible fragmentation of the mitochondrial network coupled with an increase in the presence of tumor susceptibility gene 101 (TSG101) on the mitochondrial membrane, indicative of the sorting of mitochondrial cargo into EVs. Consequently, the abundance of mitochondrial RNAs (mtRNAs) in EVs released by FaDu cells was enhanced. Notably, mtRNAs were also detectable in EVs isolated from the serum of both HNSCC patients and healthy controls. Starvation and BEZ reduced the production of EVs by cancer cells, yet the characteristic molecular profile of these EVs remained unchanged. We also found that alterations in the release of inflammatory cytokines constitute a principal response to autophagy induction. Importantly, the specific mechanism driving autophagy induction significantly influenced the composition of the EVs-associated cytokine secretome.

In this editorial, we comment on the article published in the recent issue of the World Journal of Gastroenterology. Acute liver failure (ALF) is a fatal disease that causes uncontrolled massive hepatocyte death and rapid loss of liver function. Ferroptosis and pyroptosis, cell death forms that can be initiated or blocked concurrently, can play significant roles in developing inflammation and various malignancies. However, their roles in ALF remain unclear. The article discovered the positive feedback between ferroptosis and pyroptosis in the progression of ALF, and revealed that the silent information regulator sirtuin 1 (SIRT1) inhibits both pathways through p53, dramatically reducing inflammation and protecting hepatocytes. This suggests the potential use of SIRT1 and its downstream molecules as therapeutics for ALF. Thus, we will discuss the role of ferroptosis and pyroptosis in ALF and the crosstalk between these cell death mechanisms. Additionally, we address potential treatments that could alleviate ALF by simultaneously inhibiting both cell death pathways, as well as examples of SIRT1 activators being used as disease treatment strategies, providing new insights into the therapy of ALF.

Liver fibrosis is a key and reversible stage in the progression of many chronic liver diseases to cirrhosis or hepatocellular carcinoma. Forsythiaside-A (FTA), a main compound isolated from Forsythiae Fructus, has an excellent liver protective activity. This study aims to investigate the efficacy of FTA in improving cholestatic liver fibrosis. Bile-duct-ligation (BDL) was conducted to induce liver fibrosis in mice. Hepatic collagen deposition was evaluated by Masson and Sirus red staining. The bile acid spectrum in the liver and serum was analyzed by mass spectrometry. Liver oxidative stress injury and mitochondria damage were observed by using Mito-Tracker Red fluorescence staining, transmission electron microscopy, etc. The level of ferrous iron (Fe2+) and the expression of ferroptosis-associated molecules were detected. The binding between FTA and its target protein was confirmed by Co-immunoprecipitation (Co-IP), cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR). Our results demonstrated that FTA alleviated BDL-induced liver fibrosis in mice. FTA did not decrease the elevated amount of bile acids in BDL-treated mice, but reduced the bile acid-induced mitochondrial damage, oxidative stress and ferroptosis in hepatocytes, and also induced nuclear factor erythroid 2-related factor-2 (Nrf2) activation. In Nrf2 knock-out mice, the FTA-provided protection against BDL-induced liver fibrosis was disappeared, and FTA's inhibition on mitochondrial damage, oxidative stress and ferroptosis were lowered. Further results displayed that FTA could directly bind to Kelch-like ECH-associated protein-1 (Keap1), thereby activating Nrf2. Moreover, the BDL-induced liver fibrosis was markedly weakened in liver-specific Keap1 knockout mice. Hence, this study suggests that FTA alleviated the BDL-induced liver fibrosis through attenuating mitochondrial damage and ferroptosis in hepatocytes by activating Nrf2 via directly binding to Keap1.

This editorial discusses a recently published paper in the World Journal of Gastroenterology. Our research focuses on p53's regulatory mechanism for controlling ferroptosis, as well as the intricate connection between ferroptosis and liver diseases. Ferroptosis is a specific form of programmed cell death that is de-pendent on iron and displays unique features in terms of morphology, biology, and genetics, distinguishing it from other forms of cell death. Ferroptosis can affect the liver, which is a crucial organ responsible for iron storage and meta-bolism. Mounting evidence indicates a robust correlation between ferroptosis and the advancement of liver disorders. P53 has a dual effect on ferroptosis through various distinct signaling pathways. However, additional investigations are required to clarify the regulatory function of p53 metabolic targets in this complex association with ferroptosis. In the future, researchers should clarify the mechanisms by which ferroptosis and other forms of programmed cell death contribute to the progression of liver diseases. Identifying and controlling important regulatory factors associated with ferroptosis present a promising therapeutic strategy for liver disorders.

Ferroptosis, a distinctive form of programmed cell death, has been implicated in numerous pathological conditions, and its inhibition is considered a promising therapeutic strategy. Currently, there is a scarcity of efficient antagonists for directly regulating intracellular ferrous iron. Ferritinophagy, an essential process for supplying intracellular labile iron, relies on nuclear receptor coactivator 4 (NCOA4), a selective autophagy receptor for the ferritin iron storage complex, thus playing a pivotal role in ferritinophagy. In this study, we reported a novel von Hippel-Lindau-based NCOA4 degrader, V3, as a potent ferroptosis inhibitor with an intracellular ferrous iron inhibition mechanism. V3 significantly reduced NCOA4 levels and downregulated intracellular ferrous iron (Fe2+) levels, thereby effectively suppressing ferroptosis induced by multiple pathways within cells and alleviating liver damage. This research presents a chemical knockdown tool targeting NCOA4 for further exploration into intracellular ferrous iron in ferroptosis, offering a promising therapeutic avenue for ferroptosis-related acute liver injury.

In recent years, there has been a growing concern regarding health issues arising from exposure to nanoplastics (Nps) in the natural environment. The Nps bioaccumulate within the body via the circulatory system and accumulate in the liver, resulting in damage. Previous studies have demonstrated that maltol, derived from red ginseng (Panax ginseng C.A. Meyer) as a Maillard product, exhibits hepatoprotective effects by alleviating liver damage caused by carbon tetrachloride or cisplatin. In order to explore the specific mechanism of maltol in improving hepatotoxicity induced by Nps, mice exposed to 100 mg/kg Nps were given maltol at doses of 50 and 100 mg/kg, respectively. The results showed that Nps induced an increase in the levels of liver apoptotic factors BAX and cytochrome c, a decrease in the levels of the autophagy key gene LC3 II/I, and an increase in P62. It also caused oxidative stress by affecting the Nrf2/HO-1 pathway, and a decrease in GPX4 protein expression suggested the occurrence of ferroptosis. However, treatment with maltol significantly improved these changes. In addition, maltol (2, 4, and 8 μM) also protected human normal liver L02 cells from Np (400 μg/mL)-induced damage. Our data suggest that maltol could ameliorate Np-induced L02 cytotoxicity by reducing autophagy-dependent oxidative stress, exhibiting similar protective effects in vitro as in vivo. This study helps shed light on the specific molecular mechanism of Np-induced hepatotoxicity. For the first time, we studied the protective effect of maltol on Np-induced liver injury from multiple perspectives, expanding the possibility of treatment for diseases caused by environmental pollutants.

Recently, we characterized the ferroptotic phenotype in the liver of diabetic mice and revealed nuclear factor (erythroid-derived-2)-related factor 2 (Nrf2) inactivation as an integral part of hepatic injury. Here, we aim to investigate whether sulforaphane, an Nrf2 activator and antioxidant, prevents diabetes-induced hepatic ferroptosis and the mechanisms involved. Male C57BL/6 mice were divided into four groups: control (vehicle-treated), diabetic (streptozotocin-induced; 40 mg/kg, from Days 1 to 5), diabetic sulforaphane-treated (2.5 mg/kg from Days 1 to 42) and non-diabetic sulforaphane-treated group (2.5 mg/kg from Days 1 to 42). Results showed that diabetes-induced inactivation of Nrf2 and decreased expression of its downstream antiferroptotic molecules critical for antioxidative defense (catalase, superoxide dismutases, thioredoxin reductase), iron metabolism (ferritin heavy chain (FTH1), ferroportin 1), glutathione (GSH) synthesis (cystine-glutamate antiporter system, cystathionase, glutamate-cysteine ligase catalitic subunit, glutamate-cysteine ligase modifier subunit, glutathione synthetase), and GSH recycling - glutathione reductase (GR) were reversed/increased by sulforaphane treatment. In addition, we found that the ferroptotic phenotype in diabetic liver is associated with increased ferritinophagy and decreased FTH1 immunopositivity. The antiferroptotic effect of sulforaphane was further evidenced through the increased level of GSH, decreased accumulation of labile iron and lipid peroxides (4-hydroxy-2-nonenal, lipofuscin), decreased ferritinophagy and liver damage (decreased fibrosis, alanine aminotransferase, and aspartate aminotransferase). Finally, diabetes-induced increase in serum glucose and triglyceride level was significantly reduced by sulforaphane. Regardless of the fact that this study is limited by the use of one model of experimentally induced diabetes, the results obtained demonstrate for the first time that sulforaphane prevents diabetes-induced hepatic ferroptosis in vivo through the activation of Nrf2 signaling pathways. This nominates sulforaphane as a promising phytopharmaceutical for the prevention/alleviation of ferroptosis in diabetes-related pathologies.

Autophagy is a degradation process that is evolutionarily conserved and is essential in maintaining cellular and physiological homeostasis through lysosomal removal and elimination of damaged peptides, proteins and cellular organelles. The dysregulation of autophagy is implicated in various diseases and disorders, including cancers, infection-related, and metabolic syndrome-related diseases. Propolis has been demonstrated in various studies including many human clinical trials to have antimicrobial, antioxidant, anti-inflammatory, immune-modulator, neuro-protective, and anti-cancer. Nevertheless, the autophagy modulation properties of propolis have not been extensively studied and explored. The role of propolis and its bioactive compounds in modulating cellular autophagy is possibly due to their dual role in redox balance and inflammation. The present review attempts to discuss the activities of propolis as an autophagy modulator in biological models in relation to various diseases/disorders which has implications in the development of propolis-based nutraceuticals, functional foods, and complementary therapies.

Patrinia villosa (Thunb.) Juss is one of the plant resources of the famous traditional Chinese medicine "Bai jiang cao (herba patriniae)," and it is considered to function at the liver meridian, thereby treating diseases of the liver as demonstrated by the traditional theory of TCM. Unfortunately, the therapeutic mechanism of the whole plant of PV is so far unknown.

UPLC QTOF-MS/MS was used to analyze the profile of PV. Male Sprague-Dawley rats were categorized into five groups, and PV groups (125 and 375 mg/kg) were administered by oral gavage for seven consecutive days. The model of liver injury was induced by intraperitoneal injection of 40% CCl4 oil solution. H&E staining was performed for histological evaluation. The ELISA method was used to assess the serum level of ALT, AST, and T-BIL. Serum and liver bile acid (BA) profiling was analyzed by LC-MS/MS. TUNEL-stained liver sections were used to monitor apoptosis caused by CCl4. HepG2 cells were used to detect autophagy caused by CCl4.

A total of 16 compounds were identified from the 70% methanol extract of PV. PV (125 and 375 mg/kg) could reverse the ectopic overexpression of AST, ALT, and T-BIL caused by CCl4 administration. H&E staining indicated that PV (125 and 375 mg/kg) could reduce the infiltration of inflammatory cells and restore liver tissue and hepatocyte structures. Six bile acids, including DCA, HDCA, GCA, TCA, TCDCA, and TUDCA, were significantly altered both in the serum and liver tissue after CCl4 administration, and the level of all these six bile acids was restored by PV treatment. Moreover, PV inhibited apoptosis caused by CCl4 stimulation in liver tissue and suppressed autophagy in HepG2 cells treated with CCl4.

The results in this paper for the first time reveal the alteration of the bile acid profile in CCl4-induced liver injury and demonstrate that inhibiting apoptosis and autophagy was involved in P. villosa-elicited liver protection, providing a scientific basis for the clinical utilization of P. villosa as a natural hepatic protective agent.

As a global public health issue, the treatment of acute liver injury (ALI) is severely limited due to the lack of specific drugs. In order to address the challenges, innovative strategies for selenium nanoparticles (Se NPs) with excellent antioxidant properties have been actively developed to effectively prevent ALI. However, the functional activity of Se NPs is severely affected by poor stability and bioavailability. The aim of this work is to develop a stabilization system (ASP-Se NPs) for Angelica sinensis polysaccharides modified Se NPs. The results showed that ASP-Se NPs with smaller size (62.38 ± 2.96 nm) showed good stability, specific accumulation in liver and enhanced cell uptake, thus exerting strong antioxidant and anti-inflammatory functions. The results of in vivo experiments further confirmed that ASP-Se NPs effectively prevented CCl4-induced ALI by improving liver function, inhibiting oxidative stress and inflammatory response, and liver pathological damage. This work provides a new alternative method for effectively preventing ALI and improving liver function.

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Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological mechanism and target has not yet been fully elucidated. In this study, liver fibrosis was induced by CCl4 in wild-type mice and hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- or CCl4-induced hepatocyte ferroptosis models with or without Ecm1 gene knockdown were evaluated in vitro. Subsequently, the interaction between Ecm1 and xCT and the binding kinetics of Sal B and Ecm1 were determined. We found that Sal B significantly attenuated liver fibrosis in CCl4-induced mice. Ecm1 deletion in hepatocytes abolished the antifibrotic effect of Sal B. Mechanistically, Sal B protected against hepatocyte ferroptosis by upregulating Ecm1. Further research revealed that Ecm1 as a direct target for treating liver fibrosis with Sal B. Interestingly, Ecm1 interacted with xCT to regulate hepatocyte ferroptosis. Hepatocyte ferroptosis in vitro was significantly attenuated by Sal B treatment, which was abrogated after knockdown of Ecm1 in LO2 cells. Therefore, Sal B alleviates liver fibrosis in mice by targeting up-regulation of Ecm1 and inhibiting hepatocyte ferroptosis. The interaction between Ecm1 and xCT regulates hepatocyte ferroptosis.

In humans, acute and chronic respiratory infections caused by viruses are associated with considerable morbidity and mortality. Respiratory viruses infect airway epithelial cells and induce oxidative stress, yet the exact pathogenesis remains unclear. Oxidative stress activates the transcription factor NRF2, which plays a key role in alleviating redox-induced cellular injury. The transcriptional activation of NRF2 has been reported to affect both viral replication and associated inflammation pathways. There is complex bidirectional crosstalk between virus replication and the NRF2 pathway because virus replication directly or indirectly regulates NRF2 expression, and NRF2 activation can reversely hamper viral replication and viral spread across cells and tissues. In this review, we discuss the complex role of the NRF2 pathway in the regulation of the pathogenesis of the main respiratory viruses, including coronaviruses, influenza viruses, respiratory syncytial virus (RSV), and rhinoviruses. We also summarize the scientific evidence regarding the effects of the known NRF2 agonists that can be utilized to alter the NRF2 pathway.

Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other cell death modes, plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications and posttranslational modifications (PTMs) promote anticancer drug resistance, cancer progression, and metastasis. Accumulating studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases (NSDs), cardiovascular diseases (CVDs), liver diseases, lung diseases, and kidney diseases. In this review, we first summarize the core molecular mechanisms of ferroptosis. Then, the roles of epigenetic processes, including histone PTMs, DNA methylation, and noncoding RNA regulation and PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, and ADP-ribosylation, are concisely discussed. The roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases, including cancers, NSD, CVDs, liver diseases, lung diseases, and kidney diseases, as well as the application of epigenetic and PTM modulators in the therapy of these diseases, are then discussed in detail. Elucidating the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other diseases. In addition, these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

Selenium (Se) is an indispensable trace element with versatile functions in antioxidant defense in poultry. In our previous study, we synthesized a novel type of biogenic selenium nanoparticle based on alginate oligosaccharides (SeNPs-AOS), and found that the particles are sized around 80 nm with an 8% Se content, and the dietary addition of 5 mg/kg of SeNPs-AOS could effectively alleviate the deleterious effects of heat stress (HS) in broilers, but it is still unclear whether SeNPs-AOS can improve the meat quality. Therefore, the aim of this study was to evaluate the protective effects of SeNPs-AOS on breast meat quality in heat-stressed broilers, and explore the relevant mechanisms. Birds at the age of 21 days were randomly divided into four groups with six replicates per group (eight broilers per replicate) according to a 2 × 2 experimental design, using HS (33 ± 2 °C, 10 h/day vs. thermoneutral, TN, under 23 ± 1.5 °C) and SeNPs-AOS (5 mg/kg feed vs. no inclusion) as variables. The results showed that dietary SeNPs-AOS decreased the cooking loss (p < 0.05), freezing loss (p < 0.001), and shear force (p < 0.01) of breast muscle in heat-stressed broilers. The non-targeted metabolomics analysis of the breast muscle identified 78 differential metabolites between the HS and HS + SeNPs-AOS groups, mainly enriched in the arginine and proline metabolism, β-alanine metabolism, D-arginine and D-ornithine metabolism, pantothenate, and CoA biosynthesis pathways (p < 0.05). Meanwhile, supplementation with SeNPs-AOS increased the levels of the total antioxidant capacity (T-AOC), the activities of catalase (CAT) and glutathione peroxidase (GSH-Px), and decreased the content of malondialdehyde (MDA) in the breast muscle (p < 0.05) in broilers under HS exposure. Additionally, SeNPs-AOS upregulated the mRNA expression of CAT, GPX1, GPX3, heme oxygenase-1 (HO-1), masculoaponeurotic fibrosarcoma G (MafG), MafK, selenoprotein W (SELENOW), SELENOK, ferritin heavy polypeptide-1 (FTH1), Ferroportin 1 (Fpn1), and nuclear factor erythroid 2-related factor 2 (Nrf2) (p < 0.05), while it downregulated Kelch-like ECH-associated pro-36 tein 1 (Keap1) and prostaglandin-endoperoxide Synthase 2 (PTGS2) expression (p < 0.05) in broilers under HS. These findings demonstrated that the dietary addition of SeNPs-AOS mitigated HS-induced oxidative damage and metabolite changes in the breast muscle of broilers, which may be related to the regulation of the Nrf2 signaling pathway and selenoprotein synthesis. In addition, SeNPs-AOS upregulated the breast muscle gene expression of anti-ferroptosis-related molecules in broilers under HS, suggesting that SeNPs-AOS can be used as novel Se supplements against HS in broilers.

Elaidic acid (EA, C18:1 trans) is a kind of principal Trans fatty acid (TFA) and is widely found in processed food. Pyroptosis is a form of programmed cell death, distinct from apoptosis and traditional necrosis. Excessive pyroptosis could induce body injury and serious inflammation. However, the effect of EA on pyroptosis has not been reported. In the study, we found that EA exposure caused liver damage and hepatocyte pyroptosis by testing GSDMD-N, Caspase 1, IL-18, and IL-1β in mice and HepG2 cells. Further exploring the mechanisms, we found that EA-induced pyroptosis depended on Cathepsin B (CTSB)-mediated NLRP3 inflammasome activation. Cell autophagy was closely related to lysosomes. Our study revealed that EA promoted hepatocyte autophagy, and activated autophagy induced lysosomal membrane permeabilization (LMP) and CTSB leakage. Inhibition of autophagy by 3-MA mitigated the CTSB leak, reduced the activation of the NLRP3 inflammasome, and then attenuated the EA-induced pyroptosis. In summary, these results indicated that EA induced hepatocyte pyroptosis via autophagy-CTSB-NLRP3 inflammasome pathway. The study revealed new insights into the toxicity mechanism of EA.

It is essential to further characterize liver injury aimed at developing novel therapeutic approaches. This study investigated the mechanistic basis of genipin against carbon tetrachloride (CCl4)-triggered acute liver injury concerning ferroptosis, a novel discovered modality of regulated cell death. All experiments were performed using hepatotoxic models upon CCl4 exposure in mice and human hepatocytes in vitro. Immunohistochemistry, immunoblotting, molecular docking, RNA-sequencing and ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) were conducted. CCl4 intoxication was manifested with lipid peroxidation-dictated ferroptotic cell death, together with changes in a cascade of ferroptosis-associated events and several regulatory pathways. Both the administration of genipin and ferrostatin-1 (Fer-1) significantly prevented this hepatotoxicity in response to CCl4 intoxication via upregulating GPX4 and xCT (i.e., critical regulators of ferroptosis). RNA-sequencing unraveled that arachidonic acid metabolism was considerably influenced upon genipin treatment. Accordingly, genipin treatment attenuated arachidonate 15-lipoxygenase (ALOX15)-launched lipid peroxidation in terms of UHPLC-MS/MS analysis and inflammation. In vitro, genipin supplementation rescued erastin-induced hepatocellular inviability and lipid ROS accumulation. The siRNA knockdown of GPX4 partially abrogated the protective effects of genipin on erastin-induced cytotoxicity, whereas the cytotoxicity was less severe in the presence of diminished ALOX15 expression in L-O2 cells. In conclusion, our findings uncovered that genipin treatment protects against CCl4-triggered acute liver injury by abrogating hepatocyte ferroptosis, wherein the pharmacological modification of dysregulated GPX4 and ALOX15-launched lipid peroxidation was responsible for underlying medicinal effects as molecular basis.

Cisplatin, a potent chemotherapeutic agent, is marred by severe nephrotoxicity that is governed by mechanisms involving oxidative stress, inflammation, and apoptosis pathways. The transcription factor Nrf2, pivotal in cellular defense against oxidative stress and inflammation, is the master regulator of the antioxidant response, upregulating antioxidants and cytoprotective genes under oxidative stress. This review discusses the mechanisms underlying chemotherapy-induced kidney injury, focusing on the role of Nrf2 in cancer therapy and its redox regulation in cisplatin-induced kidney injury. We also explore Nrf2's signaling pathways, post-translational modifications, and its involvement in autophagy, as well as examine redox-based strategies for modulating Nrf2 in cisplatin-induced kidney injury while considering the limitations and potential off-target effects of Nrf2 modulation. Understanding the redox regulation of Nrf2 in cisplatin-induced kidney injury holds significant promise for developing novel therapeutic interventions. This knowledge could provide valuable insights into potential strategies for mitigating the nephrotoxicity associated with cisplatin, ultimately enhancing the safety and efficacy of cancer treatment.

The accumulation of exogenous silver nanoparticles (AgNPs) will terminally bring about liver injury, including cell death, where DNA methylation tends to be a crucial epigenetic modulator. The change in the cell autophagy level verified to be closely associated with hepatocyte death has been followed with wide interest. But the molecular toxicological mechanisms of AgNPs in relation to DNA methylation, autophagy, and cell death remain inconclusive. To address the issue above, in LO2 cells treated with increasing concentrations of AgNPs (0, 5, 10, and 20 μg/mL), a cell cytotoxicity assay was performed to analyze the level of cell death, which also helped to choose an optimal concentration for next experiments. An immunofluorescence assay was used to determine the autophagic flux as well as TFEB translocation, with qRT-PCR and western blot being used to analyze the expression level of autophagy-related genes and proteins. According to our findings, in the determination of cell viability, 20 μg/mL (AgNPs) was adopted as the best working concentration. LO2 cell death, autophagy, and TFEB nuclear translocation were induced by AgNPs, which could be inhibited by lysosome inhibitor chloroquine (CQ) or siRNA specific for TFEB. Moreover, AgNP exposure led to DNA hypermethylation, with DNMT1 taking part mainly, which could be obviously prevented by 5-Aza-2'-deoxycytidine (5-AzaC) or trichostatin A (TSA) treatment or DNMT1 knockout in LO2 cells. Our studies suggest that through TFEB-dependent cell autophagy, increased DNMT1 may facilitate cell death induced by AgNPs.