Adipose tissue fibrosis, characterized by abnormal extracellular matrix deposition within adipose tissue, signifies a crucial indicator of adipose tissue malfunction, potentially leading to organ tissue dysfunction. Various factors, including a high-fat diet, non-alcoholic fatty liver disease, and insulin resistance, coincide with adipose tissue fibrosis. MicroRNAs (miRNAs) represent a class of small non-coding RNAs with significant influence on tissue fibrosis through diverse signaling pathways. For instance, in response to a high-fat diet, miRNAs can modulate signaling pathways such as TGF-β/Smad, PI3K/AKT, and PPAR-γ to impact adipose tissue fibrosis. Furthermore, miRNAs play roles in inhibiting fibrosis in different contexts: suppressing corneal fibrosis via the TGF-β/Smad pathway, mitigating cardiac fibrosis through the VEGF signaling pathway, reducing wound fibrosis via regulation of the MAPK signaling pathway, and diminishing fibrosis post-fat transplantation via involvement in the PDGFR-β signaling pathway. Notably, the secretome released by miRNA-transfected adipose-derived stem cells facilitates targeted delivery of miRNAs to evade host immune rejection, enhancing their anti-fibrotic efficacy. Hence, this study endeavors to elucidate the role and mechanism of miRNAs in adipose tissue fibrosis and explore the mechanisms and advantages of the secretome released by miRNA-transfected adipose-derived stem cells in combating fibrotic diseases.

Given the rising prevalence of liver fibrosis, there is an urgent need to improve the effective diagnostic methods and treatment of liver fibrosis. Although GPCRs are involved in various physiological and pathological processes, however, the hepatic functions of GPR56 have rarely been explored. This study aims to investigate the role and underlying mechanisms of GPR56 in liver fibrosis.

The expression of GPR56 in carbon tetrachloride (CCl4) and bile duct ligation (BDL) induced mouse liver fibrosis, as well as human fibrotic liver tissues, was assessed by western blot, qRT-PCR and immunohistochemistry. Then, WGCNA combined with GO enrichment analysis were employed to predict the functions of GPR56. Additionally, Gain- and loss-of-function models (in vitro and in vivo) were established to explore GPR56's function and the signaling pathways involved in liver fibrosis and hepatocyte pyroptosis.

GPR56 was upregulated in both human and mouse fibrotic liver tissues, as well as hepatocytes from CCl4-induced liver fibrosis mice. ROC analysis showed high diagnostic accuracy for cirrhosis (AUC = 0.895, 95% CI: 0.783-1.000). Moreover, WGCNA and GO enrichment analysis speculated that GPR56 was involved in the inflammatory response and extracellular matrix (ECM) synthesis. In vivo assays revealed that hepatocyte-specific overexpression of GPR56 attenuated, while knockdown of GPR56 exacerbated NLRP3 inflammasome-mediated pyroptosis and liver fibrosis. In vitro experiments confirmed that GPR56 inhibited hepatocyte pyroptosis, leading to the inactivation of hepatic stellate cells (HSC). Mechanistic experiments further revealed that GPR56 attenuated hepatocyte pyroptosis via inhibiting the activation of NF-κB pathway.

Our study identify GPR56 as a suppressor of hepatocyte pyroptosis and liver fibrosis, underscoring its potential as a therapeutic and diagnostic target.

This article focuses on the phosphatidylethanolamine-binding protein (PEBP) family proteins, detailing PEBP1 and PEBP4 due to limited information on PEBP2 and PEBP3, in cellular signaling pathways and research in a spectrum of pathologies, including diverse cancers, metabolic disorders, immunological diseases and a subset of organ-specific diseases. It outlines the mechanisms through which PEBP1 and PEBP4 regulate essential signaling pathways that are critical for cellular processes such as proliferation, apoptosis, and metastasis. Recent advancements have shown further understanding of these proteins' roles in pathophysiology and their potential as future therapeutic targets. The findings suggest that the impact of PEBP1 and PEBP4 on the course of different diseases has underscored their potential for more in-depth medical research and novel clinically targeted therapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global public health and economic burden worldwide in the past few decades. Epidemiological studies have shown that MASLD is a multisystem disease that is associated not only with liver-related complications but also with an increased risk of developing extrahepatic cancers. MASLD is a sexually dimorphic disease with sex hormones playing an important role in the development and progression of MASLD, especially by the levels and ratios of circulating estrogens and androgens. MASLD is associated with hormone-sensitive cancers including breast and gynecological cancer. The risk of breast and gynecological cancer is elevated in individuals with MASLD driven by shared metabolic risk factors including obesity and insulin resistance. Multiple potential mechanisms underline these associations including metabolic dysfunction, gut dysbiosis, chronic inflammation and dysregulated release of hepatokines. However, the effect of hormone therapy including hormone replacement therapy and anti-estrogen treatment on MASLD and female-specific cancers remains debatable at this time. This synopsis will review the associations between MASLD and breast and gynecological cancer, their underlying mechanisms, implications of hormonal therapies, and their future directions.

This study investigated the role of RAP1B in hepatic lipid metabolism and its implications in obesity and associated metabolic disorders, focusing on the molecular mechanisms through which RAP1B influences lipid accumulation, inflammation and oxidative stress in liver tissues and hepatocyte cell lines.

Liver-specific RAP1B-knockout (LKO) and overexpression (OE) mice were generated and fed a high-fat diet for 18 weeks to evaluate systemic and hepatic metabolic changes. Comprehensive metabolic phenotyping included measurements of body weight, body fat content, activity levels, energy expenditure (EE), respiratory exchange ratio (RER), glucose tolerance test and insulin tolerance test. RAP1B-knockdown AML12 hepatocytes were used for in vitro studies. Comprehensive transcriptome and metabolome analyses identified differentially expressed genes and key metabolic shifts. Biochemical and histological analyses were performed to assess lipid accumulation, oxidative stress and inflammatory markers.

We found that LKO mice exhibited significant reductions in body weight, fat pad size and liver mass, along with decreased hepatic lipid accumulation due to enhanced lipid breakdown. These mice demonstrated improved glucose tolerance and insulin sensitivity without changes in food intake. Liver histology showed reduced F4/80-positive macrophage infiltration, indicating decreased inflammatory cell recruitment. Additionally, markers of oxidative stress were significantly lower, and molecular analysis revealed downregulation of the MAPK(p38) and NF-κB signaling pathways, further supporting an anti-inflammatory hepatic environment. In contrast, OE mice showed increased liver weight, aggravated hepatic lipid accumulation driven by enhanced lipogenesis, worsened insulin resistance and elevated inflammation.

This study highlights RAP1B's pivotal role in hepatic metabolism and positions it as a potential therapeutic target for obesity and related metabolic disorders.

Ubiquitin-specific peptidase 24 (USP24), a deubiquitinating enzyme, regulates protein stability by removing ubiquitin. This study investigates the role of UPS24 in lipid metabolism, inflammation, and fibrosis. It also explores the effect of targeting USP24 on metabolic disorders, focusing on high-fat diet (HFD)-induced obesity and liver diseases.

This study utilized CRISPR/Cas9 to create functional knockout mice (USP24C1695A) and treated HFD-fed mice with USP24 inhibitor (USP24-i-101). The effects of USP24 inhibition or knockout on 3T3-L1 derived adipocytes, primary hepatocytes, hepatic stellate cells, and murine hepatocyte cell line AML12 (alpha mouse liver 12) cells were assessed with RNA-sequencing. Molecular mechanisms and the interaction between USP24 and PKA-Cα were studied with co-immunoprecipitation. Downstream signaling pathways involving CREB, SREBP1, PPARγ, and C/EBPβ, as well as USP24 role in liver inflammation and fibrosis, were studied using western blot and real-time PCR. Clinical and animal tissue samples were examined with immunohistochemistry to identify the correlations between USP24 and metabolic-associated liver diseases.

Knockout or inhibition of USP24 reduced body weight, lipid accumulation, inflammation, and fibrosis in HFD-fed mice. The expression of genes related to lipogenesis, inflammation, and fibrosis was downregulated in USP24C1695A mice and those treated with USP24 inhibitor (USP24-i-101). USP24 inhibition decreased lipid droplet accumulation in adipocytes and hepatocytes, suppressed inflammation in hepatocytes and AML12 cells, and reduced fibrosis in hepatic stellate cells. Mechanistically, USP24 expression was upregulated by PKA activation during adipocyte differentiation, leading to increased PKA-Cα stability and CREB phosphorylation, which promoted lipogenic gene expression. Free fatty acids (FFA) increased USP24 expression, activating NF-κB and TGFβ pathways to induce inflammation (Cox2) and fibrosis (α-SMA). USP24 was highly expressed in patients with metabolic dysfunction-associated steatohepatitis (MASH) and correlated with Cox2 and α-SMA levels.

Hepatocellular carcinoma (HCC), the most common liver cancer, has limited treatment options. The author investigated novel combinations of regorafenib (Reg) with diosmin (Dio), sulfasalazine (SZZ), or rosuvastatin (Ros) to enhance anti-HCC efficacy. Each agent potentiated Reg activity via distinct pathway modulation: Reg/Dio inhibited Akt/m-TOR and RAF/ERK; Reg/SZZ suppressed Akt/m-TOR and NF-κB; and Reg/Ros suppressed JAK/STAT3 and RAF/ERK. These findings demonstrate synergistic potential by combining Reg with drugs possessing complementary anti-inflammatory, cholesterol-lowering, or cytotoxic activities, offering promising multi-targeted therapeutic strategies for HCC.

Bone fracture activates the immune system and induces inflammation crucial for fracture healing but may also affect trauma-distant organs like the liver. Acute alcohol intoxication (AAI) dysregulates immune responses and affects organ damage post-trauma. However, the bone-liver axis and alcohol's role in this process remain poorly understood. This study explores liver inflammation and damage following fracture, with and without prior AAI. Twenty-four male C57BL/6J mice were randomly assigned to four groups (n = 6) and received either NaCl (control) or 35% ethanol via gavage. Mice underwent femur osteotomy with external fixation or sham surgery. After 24 h, liver damage was assessed using hematoxylin-eosin and activated caspase-3 staining. Liver inflammation was evaluated through CXCL1 and polymorphonuclear leukocyte (PMNL) immunostaining, cytokine gene and protein expression analyses, and immune cell profiling in the liver via flow cytometry. Western blotting assessed NF-κB and Wnt signaling. Neither fracture alone nor with AAI caused significant liver damage. However, fracture significantly increased PMNL infiltration and altered monocyte populations, effects that were amplified by AAI. The hepatic neutrophil-to-monocyte ratio significantly decreased after fracture and was absent in the fracture AAI group. CXCL1 increased post-fracture, while MCP-1 and IL-10 decreased significantly, with AAI further significantly amplifying these changes. Wnt1 and Wnt3a levels increased significantly after fracture and were further strongly elevated by AAI. AAI completely abolished fracture-induced significant β-catenin reduction and significantly increased its phosphorylation, effects that potentially involve an AAI-induced β-catenin stabilization as well as its increased degradation. NF-κB activation was significantly decreased, while A20 expression significantly increased after fracture and AAI. Fracture influences the inflammatory liver response and signaling pathways, effects which were further modulated by AAI.

Resident CD24 +LCN2 + liver progenitor cells (LPCs) reportedly contribute to the expanding ductular reaction and macrophage-mediated inflammation associated with chronic liver damage. Both ductular reactions and macrophage-driven inflammation are associated with liver fibrosis and injury in various mouse liver disorders. This study aims to investigate the molecular phenotypes of LPCs and their regulatory mechanisms in humans with non-alcoholic steatohepatitis (NASH). Single-cell RNA sequencing (scRNA-seq) datasets are used to characterize the status and molecular phenotypes of LPCs in clinical NASH samples. To elucidate the regulatory mechanisms of LPCs, CellChat and NicheNet are employed to assess cell-cell communication between LPCs and other cell types. The findings are validated using RNA sequencing datasets associated with NASH progression, NASH mouse models (CDAHFD and HFD), and human NASH liver samples. Results show that resident CD24 +LCN2 + LPCs are identified and found to be significantly enriched in NASH patients. Cell communication analyses predict strong interactions between LPCs and proinflammatory macrophage subtypes. Additionally, in NASH, the liver recruits peripheral blood mononuclear cell (PBMC)-derived macrophages and polarizes them into proinflammatory subtypes. The macrophage subtype MP-2 is identified as the primary recipient of LPC-derived signals, exhibiting marked hyperactivation of the NF-κB pathway and a strong association with liver fibrosis. Finally, the MP-2 markers COL10A1 and TPPP3 are characterized and validated. In summary, this study reveals that resident CD24 +LCN2 + LPCs are activated in NASH and contribute to fibrosis progression by promoting the activation of the proinflammatory COL10A1 +TPPP3 + macrophage subtype.

Long-term alcohol consumption is a leading global health concern, primarily due to its deleterious effects on liver function and its well-established association with hepatocellular carcinoma. Alcohol-related liver disease (ALD) encompasses a continuum-from reversible hepatic steatosis and steatohepatitis through progressive fibrosis and cirrhosis to overt hepatocellular carcinoma. Accumulating studies have revealed that the Wnt/β-catenin signaling pathway is an essential regulator in ALD pathogenesis, orchestrating diverse molecular, immunologic, and epigenetic processes. Aberrant β-catenin activity disrupts redox homeostasis, promotes chronic inflammation, drives extracellular matrix remodeling, and alters hepatocyte cell fate, thereby creating a microenvironment that is highly conducive to carcinogenesis. This article provides a systematic review of the significant function of Wnt/β-catenin signaling in ALD, emphasizing its regulatory impact on liver fat accumulation, its inflammatory role in steatohepatitis, its involvement in fibrogenesis, and its tumor-promoting effects in alcohol-related hepatocellular carcinoma. In addition, emerging therapeutic strategies that offer potential for early identification and tailored therapy of ALD are explored-including direct Wnt modulators, combinatory therapeutics, and precision medicine approaches.

Accumulating evidence has shown that elevated oxidative stress and inflammatory response leads to hepatic impairment and dysfunction of hens during the aging process. This study was conducted to investigate the potential regulatory mechanisms of Lactobacillus reuteri (L. reuteri) in alleviating hepatic oxidative stress and dysfunction induced by diquat (DQ) exposure. A total of 480 48-wk-old Jingbai hens were randomly assigned to 4 groups: control group (Con), L. reuteri group (L.R), diquat-challenged group (DQ), and L. reuteri protective group (L.R+DQ). The results demonstrated that DQ exposure induced oxidative damages and lipid metabolism disorders manifested as the elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, triglyceride (TC) contents in serum and lipid accumulation in liver. L. reuteri supplementation alleviated DQ-induced liver oxidative injury, reflected by repairing the morphology of liver and decreasing the AST and ALT activities in serum. L. reuteri decreased the hepatic malonaldehyde (MDA) accumulation and enhanced the total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activities in liver through regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) mediated antioxidant system. In addition, L. reuteri curtailed reactive oxygen species (ROS) production and mitigated the depletion of membrane potential and thus recovering mitochondrial function disturbed by DQ challenge. Moreover, L. reuteri inhibited hepatic toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) pathway activation, downregulated the pro-inflammatory-response-related gene expressions (IL-1β, TNF-α, and IL-6) and the phosphorylation levels of IκBα, and p65 in liver and thus reducing hepatic inflammatory response and apoptosis. Overall, the findings indicate that L. reuteri provides significant protection against oxidative stress, mitochondrial impairment, inflammatory response and apoptosis caused by DQ in laying hens, and highlight its potential as a therapeutic probiotic for alleviating oxidative stress and mitochondrial dysfunction to prolong the health of aging poultry.

To investigate the role of lncRNA Snhg6 in liver fibrosis, delivered by resveratrol-stimulated macrophage exosomes.

Resveratrol-stimulated and unstimulated exosomes were generated from RAW 264.7 cells, confirmed by electron microscopy, nanoparticle analysis, and Western blotting. JS1 cells were used as an HSC model, activated with TGF-β1 and treated with exosomes. Exosome uptake was observed via confocal microscopy, and acta2 expression was measured with immunofluorescence. RNA sequencing and RT-qPCR were used to analyze exosomal lncRNA profiles. KEGG GSEA enrichment was conducted on differentially expressed genes, and nf-κb expression was detected in HSCs using WB. Serum from liver fibrosis patients was analyzed for SNHG6 levels.

Resveratrol-stimulated exosomes inhibited TGF-β1-induced HSC activation, with 132 differentially expressed lncRNAs, including upregulated Snhg6. NF-κB signaling was downregulated. Silencing Snhg6 weakened this inhibitory effect.

Resveratrol-stimulated macrophage exosomes may inhibit liver fibrosis by delivering lncRNA Snhg6, which suppresses the NF-κB pathway.

Mengding yellow bud polyphenols (MYBPs), as a plant active ingredient that may protect the liver, have not yet been elucidated for the potential molecular mechanism in preventing carbon tetrachloride (CCl4) induced acute liver injury (ALI) in mice. The MYBPs monomers compounds were explored by the high-performance liquid chromatography (HPLC). Mice were administered silymarin (100 mg/kg b.w.) or MYBPs (50 and 100 mg/kg b.w.) 2 weeks prior to CCl4-induced ALI. The liver function indexes, histopathological observation, biochemical indexes, and mRNA and protein expressions were determine. The MYBPs effectively reduced the mice liver weights, liver indexes, liver pathological injury, and the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), and total cholesterol (TC). Similarly, the MYBPs decreased the interleukin (IL)-6, IL-12, tumor necrosis factor-α (TNF-α), and interferon (IFN)-γ serum levels, reduced the liver tissues myeloperoxidase (MPO) and malondialdehyde (MDA) levels, and elevated the superoxide dismutase (SOD) and glutathione (GSH) levels. The cuprozinc-superoxide dismutase (Cu/Zn-SOD), manganese-superoxide dismutase (Mn-SOD), catalase (CAT), and B-cells inhibitor-α (IκB-α) expressions markedly increased. Additionally, the MYBPs significantly decreased the nuclear factor (NF)-κB, TNF-α, IL-1 beta, inducible NOS (iNOS), and cyclooxygenase (COX)-2 expressions. HPLC showed that MYBPs contained gallic acid (GA), (-)-epigallocatechin (EGC), epigallocatechin gallate (EGCG), and (-)-epicatechin gallate (ECG). Briefly, MYBPs effectively prevented mice CCl4-induced ALI by inhibiting oxidative stress and inflammatory pathways, and its preventive effect was dose-dependent with its concentration. This study provided a scientific basis for the development of MYBPs into functional food as well as a new idea for clinical prevention and treatment of human ALI. Practical Application: MYBPs can alleviate CCl4-induced Hepatotoxicity by raising the antioxidant and antiinflammatory status and upregulating the antioxidant and antiinflammatory-related genes and protein.

Severe immune responses regulate the various clinical hepatic injuries, including autoimmune hepatitis and acute viral hepatitis. N6-methyladenosine (m6A) modification is a crucial regulator of immunity and inflammation. However, the precise role of YTHDF1 in T cell-mediated hepatitis remains incompletely characterized. To address this, we utilized Concanavalin A (ConA)-induced mouse liver damage as an experimental model for T cell-mediated hepatitis. Our findings found that hepatic YTHDF1 protein rapidly decreased during ConA-induced hepatitis, and YTHDF1-deficient (Ythdf1 -/- ) mice showed more susceptibility to ConA-induced liver injury, along with an intensified inflammatory storm accompanied by aggravated hepatic inflammatory response via ERK and NF-κB pathways. Interestingly, hepatic-specific over-expression or deletion of YTHDF1 exhibited redundancy in ConA-induced liver injury. Validation in bone marrow chimeric mice confirmed the necessity of YTHDF1 in hematopoietic cells for controlling the response to ConA-induced hepatitis. Additionally, our data revealed that YTHDF1 deletion in macrophages exacerbated the inflammatory response induced by lipopolysaccharide. In summary, our study uncovered that YTHDF1 deficiency exacerbates the immune response in ConA-induced hepatitis by modulating the expression of inflammatory mediators, highlighting the potential of YTHDF1 as a therapeutic target for clinical hepatitis.

An existing study has underlined the involvement of Methyltransferase Like 3 (METTL3) and its mediated N6-methyladenosine (m6A) modification on zinc finger MYM-type containing 1 (ZMYM1) in cancers, and we aimed to explore their implication in liver hepatocellular carcinoma (LIHC). The levels of METTL3 and ZMYM1 in LIHC cells were gauged via qPCR. The involvement of METTL3 in LIHC progression was explored via assays in vitro and in vivo, and the mechanisms underlying the effects of METTL3 on LIHC were explored via m6A methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) and confocal immunofluorescence assays. METTL3, the m6A methyltransferase of interest, expressed relatively higher in LIHC. The promoting effects of METTL3 on LIHC progression were confirmed both in vitro and in vivo, and the relevant mechanisms maybe related to ZMYM1, a target of METTL3. Such effects of METTL3-m6A-ZMYM1 axis on the progression of LIHC were confirmed to be related to the inactivation of RAS/ERK/c-FOS pathway and the reduction in E-cadherin expression yet the elevation in N-cadherin and Vimentin expressions, therefore accelerating the metastasis in LIHC. Our study highlighted the possible involvement of METTL3-mediated m6A modification in LIHC and explored METTL3-m6A-ZMYM1 axis as a possible therapeutic target for the anti-metastatic strategy against LIHC.

Fibrosis, the excessive production and disorganised deposition of extracellular matrix proteins, can occur in any organ system, disrupting functionality and causing fatality. The number, efficacy and safety of antifibrotic drugs are incredibly limited. Therapeutics which elevate intracellular cyclic adenosine monophosphate (cAMP) offer a potential solution. In this review, we present the signalling mechanisms involved in fibrosis pathophysiology, how cAMP and its effectors might interact with these pathways, and the current preclinical and clinical efforts in this field. cAMP elevating agents have the potential to be future antifibrotic drug candidates, but further studies are required, particularly to develop tissue specific therapeutics.

The present research was performed to examine the possible capability of allopurinol to prevent developing hepatocellular carcinoma (HCC) and to explore the fundamental mechanisms that control the hepatoprotective effect considering the enormous impact of HCC on patients' quality of life. Male Sprague Dawely rats were given i.p. injection of thioacetamide (TAA) (200 mg/kg) twice a week for 16 weeks in order to induce HCC. The histological analysis and assessment of the serum levels of liver function indicators verified the development of HCC. Two regimens of allopurinol (100 mg/kg, p.o.) were used; the first involved giving it concurrently with TAA from week 13 to week 16, and the second regimen started from week 9 to week 16. Chronic TAA damage was associated with considerable overexpression of the profibrogenic cytokine TGF-β, degradation and nuclear translocation of NF-κB, which released a number of inflammatory mediators, and upregulation of the NLRP3/caspase1 pathway. Administration of allopurinol demonstrated considerable enhancements in liver function and oxidative balance. Moreover, pathological characteristics like cirrhosis, dysplastic changes, and HCC nodules were greatly diminished. Allopurinol via suppressing TGF-β expression, inhibiting NF-κB nuclear translocation, and restricting inflammatory NLRP3/caspase1/IL-1β pathway was able to protect against TAA-induced liver damage, and it could be a promising therapy for HCC.

The pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) involves multiple pathophysiological processes, including abnormal lipid metabolism, insulin resistance, oxidative stress, endoplasmic reticulum stress, inflammatory response, and fibrosis. These factors interact to form a complex network and the development of synergistic and pleiotropic drug modalities targeting multiple pathogenesis of MASH may have a better therapeutic effect. Herein, the bifunctional proteolytic targeting chimeras (PROTAC) technology was utilized for developing pleiotropic drugs for MASH treatment. We constructed a Keap1-recruiting degrader KB-3 which stabilizes the natural Keap1 target Nrf2 and degrades BRD4 synergistically, exhibiting combined therapeutic advantages against MASH-related pathologies. Experimental results confirmed that KB-3 could effectively alleviate MASH in mice by improving lipid metabolic disorder, enhancing the defense against oxidative stress, reducing inflammation, and delaying the progression of liver fibrosis. Such Keap1-recruiting degrader offering a single-molecular approach with polypharmacology effects may be an attractive strategy for the treatment of multifactorial disease.

Tumor necrosis factor receptor-associated factor-6 (TRAF6) is a well-established upstream regulator of the IKK complex, essential for the modulation of the NF-κB (nuclear factor kappa B) signaling pathway. Aberrant activation of TRAF6 has been strongly implicated in the pathogenesis of various cancers, including hepatocellular carcinoma (HCC). The speckle type BTB/POZ protein (SPOP), an E3 ubiquitin ligase substrate-binding adapter, constitutes a significant component of the CUL3/SPOP/RBX1 complex, which is closely linked to tumorigenesis. In this study, we demonstrated that the E3 ubiquitin ligase SPOP shielded TRAF6 from proteasomal degradation, leading to the hyperactivation of the NF-κB pathway. Notably, a liver cancer-associated S119N mutation in SPOP resulted in a failure to mediate the ubiquitination and subsequent degradation of TRAF6. Moreover, both gain-of-function and loss-of-function experiments revealed that SPOP inhibits the proliferation and invasion of HCC cells through the TRAF6-NF-κB axis in vitro and in vivo. Taken together, our findings elucidate the underpinning mechanism by which SPOP negatively regulates the stability of the TRAF6 oncoprotein, thus offering a new therapeutic target for HCC intervention.

Hepatocellular carcinoma (HCC), originating from hepatocytes, is the most common type of primary liver cancer. HCC imposes a significant global health burden with high morbidity and mortality, making it a critical public concern. Surgical interventions, including hepatectomy and liver transplantation, are pivotal in achieving long-term survival for patients with HCC. Additionally, ablation therapy, endovascular interventional therapy, radiotherapy, and systemic anti-tumor therapies are commonly employed. However, these treatment modalities are often associated with considerable challenges, including high postoperative recurrence rates and adverse effects. Traditional Chinese medicine (TCM) and natural products have been utilized for centuries as a complementary approach in managing HCC and its complications, demonstrating favorable clinical outcomes. Various bioactive compounds derived from TCM and natural products have been identified and purified, and their mechanisms of action have been extensively investigated. This review aims to provide a comprehensive and up-to-date evaluation of the clinical efficacy of TCM, natural products and their active constituents in the treatment and management of HCC. Particular emphasis is placed on elucidating the potential molecular mechanisms and therapeutic targets of these agents, including their roles in inhibiting HCC cell proliferation, inducing apoptosis and pyroptosis, suppressing tumor invasion and metastasis, and restraining angiogenesis within HCC tissues.

The liver plays a critical role in maintaining homeostasis, and its dysfunction can lead to severe conditions like acute liver injury (ALI), which is primarily caused by viral infections, toxins, and oxidative stress. Reactive oxygen species (ROS), especially hydrogen peroxide (H₂O₂), significantly drive hepatocyte injury, initiating oxidative stress and inflammation. Current antioxidants, such as N-acetylcysteine (NAC) and superoxide dismutase (SOD), show limited clinical efficacy due to poor targeting, instability, and toxicity. Catalase (CAT), an essential enzyme for H₂O₂ decomposition, represents a promising therapeutic for ALI; however, its clinical application faces challenges in stability, rapid degradation, and insufficient targeting. Here, a novel nanocapsule-based CAT delivery system (n(CAT)) is presented, formed through in situ radical polymerization using 2-methacryloyloxyethyl phosphorylcholine (MPC) and N-(3-aminopropyl)-methacrylamide hydrochloride (APM). This strategy significantly enhances CAT's stability, retains enzyme activity, and improves selective liver accumulation, particularly at inflammation sites. The results demonstrate that n(CAT) effectively reduces oxidative stress, minimizes inflammation, and facilitates liver repair in ALI and ischemia-reperfusion injury (IRI) models. These findings highlight the potential of n(CAT) as a promising platform for advanced antioxidant therapies targeting liver diseases, including hepatitis.

Simultaneous abuse of ethanol and methamphetamine (METH) causes severe liver damage through oxidative stress and inflammation. This study evaluated the antifibrotic effects of gold nanoparticles (AuNPs) coadministered with the β-blocker carvedilol (CARV) against liver damage in rats. Male Wistar rats received 30% ethanol (7 g/kg) daily for 28 days, with METH (10 mg/kg) administered on the 22nd and 28th days. Liver damage was assessed using serum hepatic enzymes, glutathione (GSH) levels, malondialdehyde (MDA) formation, myeloperoxidase (MPO) inhibition, and histopathological analysis, including H&E, Picrosirius Red staining, immunofluorescence, and transmission electron microscopy. Cytokine levels were measured in liver tissue samples. In vitro, RAW 264.7 macrophages were induced to polarize into M1 and M2 phenotypes and cocultured with AuNPs + CARV-treated 3T3 cells, analyzed by rtPCR. AuNPs + CARV effectively protected the liver by modulating interactions between hepatic stellate cells (HSCs) and Kupffer cells, promoting an antifibrotic immune response driven by M1 macrophages. This was indicated by downregulation of profibrotic M2 macrophages and upregulation of M1 macrophages, shown by an increased CD86/CD163 ratio and reduced levels of IL-1β, TNF-α, TGFβ, AKT, and PI3K., pointing an attenuated liver inflammation. These results suggest that AuNPs combined with CARV could potentially serve as a therapy for alcohol and METH-induced liver fibrosis by targeting M2 macrophages.

Hepatocellular Carcinoma (HCC), a highly prevalent malignancy, poses a significant global health challenge. Its pathogenesis is intricate and multifactorial, involving a complex interplay of environmental and genetic factors. Viral hepatitis, excessive alcohol consumption, and cirrhosis are known to significantly elevate the risk of developing HCC. The underlying biological processes driving HCC are equally complex, encompassing aberrant activation of molecular signaling pathways, dysregulation of hepatocellular differentiation and angiogenesis, and immune dysfunction. This review delves into the multifaceted nature of HCC, exploring its etiology and the intricate molecular signaling pathways involved in its development. We examine the role of immune dysregulation in HCC progression and discuss the potential of emerging therapeutic strategies, including immune-targeted therapy and tumor-associated macrophage interventions. Additionally, we explore the potential of traditional Chinese medicine (TCM) monomers in inhibiting tumor growth. By elucidating the complex interplay of factors contributing to HCC, this review aims to provide a comprehensive understanding of the disease and highlight promising avenues for future research and therapeutic development.

Liver fibrosis is a key pathological process in chronic liver diseases, regulated by various cytokines and signaling pathways. Among these, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway plays a significant role in the initiation and progression of liver fibrosis. Recently, natural products have garnered attention as potential anti-fibrotic agents. This review highlights recent studies on how natural products, including flavonoids, terpenoids, polysaccharides, phenols, alkaloids, quinones, phenylpropanoids, steroids, and nitrogen compounds, mitigate liver fibrosis by modulating the NF-κB signaling pathway. Specifically, it examines how these natural products influence NF-κB activation, nuclear translocation, and downstream signaling, thereby inhibiting inflammatory responses, reducing apoptosis, and regulating hepatic stellate cell (HSC) activity, ultimately achieving therapeutic effects against liver fibrosis. A deeper understanding of the mechanisms by which natural products regulate the NF-κB signaling pathway can provide crucial theoretical foundations and valuable insights for the development of novel anti-fibrotic drugs.

Alpha-tocopherol (vitamin E) is a plant-derived dietary lipid that is essential for the health of most animals, including humans. Originally discovered as a fertility factor in rodents, the primary health-promoting properties of the vitamin in humans was shown to be protection of neuromuscular functions. Heritable vitamin E deficiency manifests in spinocerebellar ataxia that can be stabilized by timely supplementation with high-dose α-tocopherol. The molecular basis for α-tocopherol's biological activities has been attributed primarily to the vitamin's efficacy in preventing lipid peroxidation in membranes and lipoproteins, but the possibility that the vitamin possesses additional biological activities has been postulated and debated in the literature without conclusive resolution. We designed and synthesized a novel analog of α-tocopherol, 6-hydroxymethyl α-tocopherol (6-HMTC), which retains most of the vitamin's structural, physical, and biochemical properties, yet lacks measurable radical-trapping antioxidant activity. 6-HMTC bound to the tocopherol transfer protein with high (nanomolar) affinity, like that of the natural vitamin, attesting to the analog's preservation of structural integrity. Yet, 6-HMTC did not inhibit lipid peroxidation or associated ferroptotic cell death. Notably, 6-HMTC modulated the expression of some genes in a manner essentially identical to that exhibited by α-tocopherol. These findings support the notion that α-tocopherol modulates gene expression via an antioxidant-independent mechanism.

Aspartame is a widely used artificial sweetener in food and beverages. Its safety concerns and potential carcinogenic risks have garnered increasing attention. This study aims to systematically explore the carcinogenic potential and mechanisms of aspartame on the liver through a comprehensive analysis based on network toxicology, mendelian randomization, molecular dynamics and single-cell RNA sequencing.

ProTox 3.0 and ADMEtlab 2.0 platforms were used to predict the toxicity and drug metabolism levels of aspartame. Network toxicology methods were employed to investigate the pathogenic pathways and mechanisms of aspartame in liver cancer. Mendelian randomization (MR) was used to verify the causal relationship between aspartame's carcinogenic targets and liver cancer. Furthermore, molecular docking and molecular dynamics (MD) simulations were conducted to explore the binding efficiency and stability of aspartame with the validated targets from MR. Single-cell technology further explores which types of liver cells have the highest expression of CASP1.

Combining the results from two prediction platforms, it was found that aspartame exhibits significant neurological, nephrotoxic, and hepatotoxic effects. Network toxicology results indicated that aspartame promotes the development of liver cancer by affecting multiple key proteins and regulatory factors PTGS2, IL1β and CASP1, in the Necroptosis, NF-κB and TNF signaling pathways. MR was used to discover that among the core targets of aspartame, REN, HLA-A, CASP1, and MME have causal relationships with liver cancer, while CASP1 is a risk factor for liver cancer. The binding affinity of aspartame to these four proteins was investigated by molecular docking, and it was found that the binding to CASP1 was the strongest at -18.45 kJ/mol. MD further verified that over a 50 ns period, the protein-target complex of aspartame and CASP1 exhibited excellent binding stability. Additionally, the single-cell sequencing found that CASP1 is most highly expressed in endothelial cells. In summary, these findings suggested that aspartame may increase the possibility of liver cancer by modulating the CASP1 protein.

This study identifies CASP1 as a potential target for aspartame-induced liver cancer, which is of a significant public health importance. The potential carcinogenic risk of aspartame and reliability need to be re-evaluated. The study provides a new method for assessing the safety of food additives and offers novel scientific insights into the toxicological effects of aspartame. Furthermore, subsequent experimental validation is crucial for further research into the carcinogenic mechanisms of aspartame.

The nitrate pollution has become an increasingly serious environmental problem worldwide, and the toxic effects of elevated nitrate levels in the environment on aquatic animals remain to be elucidated. The purpose of the present study was to investigate the mechanisms of liver injury to tadpoles after exposure to nitrate from embryonic to metamorphic climax and to assess the recovery process of liver function after cessation of exposure. In the group with continuous nitrate exposure, the livers and thyroid of tadpoles showed remarkably histological lesions, of this with structural disorganization of the hepatocytes, cellular atrophy, and fibrosis, as well as significant reduction in the follicular and colloidal area of the thyroid. Meanwhile, the expression levels of genes related to inflammatory signaling pathways, such as TLR2, TLR6 and NF-κB, were significant elevated. After termination of exposure at Gs23, liver damage (histologic, ultrastructural, and molecular levels) was almost completely recovered, whereas thyroid gland damage was irreversible. Overall, this study shed light on the harmful effects of nitrate pollution on amphibian health and emphasizes the importance of controlling nitrate emissions in the environment.

Background/Objectives: Liver inflammatory diseases are a major global health burden and are often exacerbated by inflammation driven by lipopolysaccharides (LPS) through toll-like receptor 4 signaling. This study evaluates the anti-inflammatory effects of psilocybin and eugenol in an LPS-induced liver inflammation model in C57BL/6J mice. Methods: Mice were treated with psilocybin (0.88 mg/kg) and/or eugenol (17.59 mg/kg) either before (pre-treatment) or after (post-treatment) LPS injection. Results: Psilocybin and eugenol, individually and in combination, significantly reduced the LPS-induced mRNA levels of pro-inflammatory cytokines, with post-treatment administration exhibiting stronger effects than pre-treatment. Psilocybin alone displayed the most pronounced anti-inflammatory response, especially for IL-1β, IL-6, and MCP-1, while its combination with eugenol in 1:50 ratio demonstrated similar results, with strongly reduced COX-2 and TNF-α. Histological analysis revealed improved nuclear circularity and reduced inflammatory infiltration in the treatment groups. Eugenol alone showed potential adverse effects, including increased MCP-1 and GM-CSF, but this was mitigated by the co-administration of psilocybin. Conclusions: These findings highlight psilocybin and its combination with eugenol as promising therapies for hepatic inflammation, suggesting their application in treating acute and chronic liver diseases. Future research should explore their long-term effects, the mechanisms underlying their anti-inflammatory actions, and their therapeutic efficacy in humans.

Liver fibrosis (LF) is characterized by excessive production of reactive oxygen species (ROS), abnormal activation of hepatic stellate cells (HSCs), and subsequent extracellular matrix (ECM) deposition. The complexity of multiple interrelated pathways involved in this process makes it challenging for monotherapy to achieve the desired therapeutic effects. To address this issue, this study designs a ROS-activated heterodimer conjugate (VTO) to collaboratively alleviate LF. Additionally, a biomimetic high-density lipoprotein is utilized for encapsulation, resulting in the formation of PL-VTO, which enables natural liver targeting. Once PL-VTO is delivered to the fibrotic liver, it can respond and release both parent drugs upon encountering the high ROS microenvironment, effectively scavenge ROS, induce quiescence of activated HSCs, and reduce collagen deposition, ultimately reversing LF. Overall, this study presents a feasible and versatile nanotherapeutic approach to enhance the prodrug-driven treatment of LF.

This study aims to evaluate the therapeutic potential of tubeimoside I (TBMS1), a monomer compound extracted from the tubers of Chinese herb Bolbostemma paniculatum (Maxim). Franquet (Cucurbitaceae), in the treatment of liver cancer. Specifically, we sought to elucidate the underlying mechanisms through which TBMS1 exerts its anticancer effects.

The effects of TBMS1 on the viability, proliferation, and apoptosis of two liver cancer cell lines, MHCC97-H and SNU-449, were comprehensively assessed using Cell Counting Kit-8 (CCK-8), colony formation, 5-ethynyl-2'-deoxyuridine (EDU) assay, and flow cytometry assays. To uncover the molecular mechanisms, RNA sequencing was performed to identify the downstream targets of TBMS1. Additionally, we utilized network pharmacology to predict TBMS1 targets in liver cancer and employed Venn diagram analysis to integrate these predictions with our experimental findings. Pathway enrichment analysis was conducted using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases to elucidate the biological processes involved. Furthermore, a subcutaneous xenograft tumor model was established to investigate the in vivo antitumor efficacy of TBMS1.

In vitro experiments demonstrated that TBMS1 significantly enhanced cell apoptosis and inhibited the growth of liver cancer cells. Both network pharmacology predictions and RNA-seq analyses revealed that the downstream target genes of TBMS1 were highly enriched in the NF-κB signaling pathway. Notably, we observed a significant upregulation of TNFα-induced protein 3 (TNFAIP3) expression with increasing concentrations of TBMS1. In vivo studies further confirmed that TBMS1 treatment dramatically reduced the volume and weight of liver cancer tumors compared to controls.

Our study provides compelling evidence that TBMS1 suppresses liver cancer progression by inactivating the NF-κB pathway and regulating TNFAIP3 expression. These findings offer novel insights and a theoretical basis for the development of targeted therapies for liver cancer.

Cichorium intybus is a traditional medicinal herb for hepatitis treatment in China and Europe. Sesquiterpene lactones are the main active ingredients in C. intybus. However, their structure-activity relationship (SAR) and molecular mechanisms of anti-inflammatory and hepatoprotective effects require further elucidation.

To identify new sesquiterpene lactones from C. intybus, and further evaluate their anti-inflammatory effects, SAR, and mechanisms of anti-inflammatory and hepatoprotective properties.

Identification of sesquiterpene lactones from C. intybus using chromatographic fractionation, NMR, and mass spectrometry. The repression of inflammation was evaluated in RAW264.7 macrophages incubated with LPS. Western blotting was employed to investigate the anti-inflammatory mechanisms. The hepatoprotective effect was measured in LPS/D-galactosamine (D-GalN)-induced acute hepatitis in mice.

We identified 3 new sesquiterpene lactones and 15 known analogues from C. intybus. SAR analysis showed that the α-methylene-γ-lactone moiety was essential for their anti-inflammatory properties. Furthermore, 8-deoxylactucin was identified as the most potent anti-inflammatory component in LPS-induced RAW264.7 macrophages by reduction of nitric oxide production via inhibiting iNOS expression, and suppression of IL-1β, IL-6, and TNF-α expression. Mechanistically, 8-deoxylactucin not only blocked LPS-induced IKKα/β phosphorylation, IκBα phosphorylation and degradation, and NF-κB nuclear accumulation, but also enhanced NRF2 expression and nuclear translocation, HO-1 and NQO1 expression, and reduced ROS generation in vitro. In vivo, 8-deoxylactucin mitigated LPS/D-GalN-induced acute hepatitis, which manifested as reduction in inflammatory infiltration, live injury, serum levels of AST and ALT, and production of pro-inflammatory cytokines and 4-hydroxynonenal.

8-Deoxylactucin, the sesquiterpene lactone isolated from C. intybus, exerted anti-inflammatory and hepatoprotective effects by blocking NF-κB activation and enhancing NRF2 activation.

Hepatic osteodystrophy (HOD) is an important public health issue that severely affects human health. The pathogenesis of HOD is complex, and exposure to environmental pollutants plays an important role. Di-(2-ethylhexyl) phthalate (DEHP) is a persistent environmental endocrine toxicant that is present in many products, and the liver is an important target organ for its toxic effects. Our research aimed to investigate the effects of DEHP on HOD, and to reveal the underlying mechanisms and the potential key preventive approaches.

The daily intake EDI of DEHP and bone density indicators for men and women from 2009 to 2018 were screened and organized from the NHANES database to reveal the population correlation between EDI and BMD; C57BL/6 female and male mice were selected to construct an animal model of DEHP induced HOD, exploring the fuchtions and mechanisms of DEHP on osteoporosis; the novel small molecule inhibitor imICA was used to inhibit the process of DEHP induced osteoporosis, further exploring the targeted inhibition pathway of DEHP induced HOD.

Male and female populations were exposed to a relatively lower concentration of DEHP, and that only the male population exhibited a negative correlation between DEHP exposure and bone mineral density. An in vivo study confirmed that a low dose of DEHP caused liver lesions, disrupted liver function, and induced osteoporosis in male but not female C57BL/6J mice. Regarding the molecular mechanisms, a low dose of DEHP activated the hepatic 14-3-3η/nuclear factor κB (NF-κB) positive feedback loop, which in turn modified the secretory proteome associated with bone differentiation, leading to HOD. Finally, we revealed that targeting the 14-3-3η/ NF-κB feedback loop using our novel 14-3-3η inhibitor (imICA) could prevent DEHP-induced HOD.

A low dose of DEHP activated the hepatic 14-3-3η/ NF-κB positive feedback loop, which in turn modified the secretory proteome associated with bone differentiation and elevated IL-6 and CXCL1 levels, leading to HOD. Targeted 14-3-3η/NF-κB feedback loop using our novel 14-3-3η inhibitor, imICA, prevented DEHP-induced HOD.

A new ursane triterpenoid, actichinone (3-oxo-2α,24-dihydroxyurs-12-en-28-oic acid, 1), was isolated from the roots of a kiwi plant Actinidia chinensis Planch, together with 18 known triterpenoids (2-19). The structure of actichinone (1) was established by extensive spectroscopic analysis. Actichinone (1) showed the most potent lipid-lowering activity in the oleic acid (OA)-induced primary mouse hepatocytes and the structure-activity relationships (SARs) were analyzed. Chemical semi-synthesis of actichinone (1) was achieved by selective oxidation of the major compound 2. Actichinone (1) exhibited significant alleviation of non-alcoholic fatty liver disease (NAFLD) in a high-fat with methionine and choline deficiency diet (HFMCD)-fed mice model, by regulating lipid accumulation and inflammatory response probably via the AMPK/SREBP-1c/PPAR-α and IKK/IκB/NF-κB signaling pathways. This study provides a promising lead compound and a new insight into the development of novel anti-NAFLD agents based on the pentacyclic triterpenoid family, and is expected to promote the high value-added comprehensive application of the A. chinensis plants.