Chronic liver injury causing liver fibrosis is a major cause of morbidity and mortality worldwide. Targeting the suppression of hepatic stellate cell (HSC) activation is recognized as an effective strategy for the treatment of liver fibrosis. Ellagic acid (EA), a natural polyphenol product isolated from fruits and vegetables, possesses many biological functions. Here, EA exerts its antifibrotic activity by inducing ferroptotic cell death of activated HSCs, which is accompanied by redox-active iron accumulation, lipid peroxidation, and GSH depletion in CCl₄ mice and human LX-2 cells. The specific ferroptosis inhibitor ferrostatin-1 prevented EA-induced ferroptotic cell death. Mechanistically, EA impairs the formation of vesicle-associated membrane protein 2 (VAMP2)/syntaxin 4 and VAMP2/synaptosome-associated protein 23 complexes by suppressing VAMP2 expression by enhancing its degradation in a proteasome-dependent pathway. This leads to the impairment of ferroportin (FPN, an iron exporter) translocation and intracellular iron extrusion. Interestingly, VAMP2 overexpression inhibits the role of EA in blocking FPN translocation and increasing intracellular ferritin content (an iron storage marker). In contrast, VAMP2 knockdown shows a synergistic effect on EA-mediated ferroptotic events in both HSCs. Additionally, HSC-specific overexpression of VAMP2 impaired EA-induced HSC ferroptosis in mouse liver fibrosis, and HSC-specific VAMP2 knockdown increased the inhibitory effect of EA on fibrosis. Taken together, our data suggest that the natural product EA exerts its antifibrotic effects by inducing FPN-dependent ferroptosis of HSCs by disrupting the formation of SNARE complexes, and EA will hopefully serve as a prospective compound for liver fibrosis treatment.

Liver fibrosis is a chronic liver injury resulting from factors like viral hepatitis, autoimmune hepatitis, non-alcoholic steatohepatitis, fatty liver disease, and cholestatic liver disease. Liver transplantation is currently the gold standard for treating severe liver diseases. However, it is limited by a shortage of donor organs and the necessity for lifelong immunosuppressive therapy. Mesenchymal stem cells (MSCs) can differentiate into various liver cells and enhance liver function when transplanted into patients due to their differentiation and proliferation capabilities. Therefore, it can be used as an alternative therapy for treating liver diseases, especially for liver cirrhosis, liver failure, and liver transplant complications. However, due to the potential tumorigenic effects of MSCs, researchers are exploring a new approach to treating liver fibrosis using extracellular vesicles (exosomes) secreted by stem cells. Many studies show that exosomes released by stem cells can promote liver injury repair through various pathways, contributing to the treatment of liver fibrosis. In this review, we focus on the molecular mechanisms by which stem cell exosomes affect liver fibrosis through different pathways and their potential therapeutic targets. Additionally, we discuss the advantages of exosome therapy over stem cell therapy and the possible future directions of exosome research, including the prospects for clinical applications and the challenges to be overcome.

Background: Hepatocellular carcinoma (HCC) is a malignant tumor with poor prognosis. N6-methyladenosine (m6A) modification has dual biological functions in RNA modification and plays an important role in HCC. Methods: The GEO, TCGA, ONCOMINE, UALCAN, GEPIA, Kaplan–Meier plotter, cBioPortal for Cancer Genomics, STRING and TIMER2 databases were used for bioinformatic analyses. Quantitative polymerase chain reaction and western blotting were used to detect the expression of m6A regulators in HCC tissues. Results: The transcription of m6A regulators was upregulated in patients with HCC, and overexpression of YTHDF1/2, YTHDC1, RBM15 and METTL3 was significantly correlated with clinical stages of HCC. In addition, downregulation of ZC3H13 and METTL14 and upregulation of other m6A regulators were associated with a poor prognosis. A high mutation rate (89%) of m6A regulators was also observed in patients with HCC, and mutations in methylation regulators were associated with poor overall survival and disease-free survival. Finally, the expression of the YTHDF family was significantly associated with immune infiltration in the HCC microenvironment. Conclusion: m6A regulators and programmed death-ligand 1 may play an important role in the tumorigenesis and immune invasion and escape of HCC and may be risk factors affecting the survival of patients with HCC.

Objective: The purpose of this study is to investigate potential associations between body fat composition and postoperative outcomes in patients with hepatectomy or liver transplantation. Methods: Three online databases, including Embase, PubMed, and the Cochrane Library, were thoroughly searched for literature describing the relationship between body fat composition and outcomes of patients with liver surgery from the start of each database to 29 October 2023. The Newcastle–Ottawa Scale was used to rate the quality of the studies. Results: This analysis included a total of 29 articles with a combined patient cohort of 6435 individuals. The results demonstrated that patients with high intramuscular fat content (IMFC) had significantly inferior overall survival (OS) [hazard ratio (HR): 2.07, 95% CI: 1.69–2.53, P <0.001] and recurrence-free survival (RFS) (HR: 1.61, 95% CI: 1.20–2.16, P =0.002) and a higher risk of major complications (HR: 2.20, 95% CI: 1.59–3.05, P <0.001). We also found that the presence of high visceral-to-subcutaneous fat tissue ratio (VSR) in patients with liver surgery was significantly related to poorer OS (HR: 1.70, 95% CI: 1.44–2.00, P <0.001) and progression-free survival (PFS) (HR: 1.29, 95% CI: 1.11–1.50, P =0.001) and a higher major complication rate (HR: 2.31, 95% CI: 1.17–4.56, P =0.016). Besides, the synthesized findings indicated there is no significant correlation between visceral fat tissue and survival outcomes or postoperative complications. Conclusion: In summary, preoperative IMFC and VSR have the potential to forecast poorer OS and RFS and a higher risk of complications for patients undergoing hepatectomy or liver transplantation.

Background Hepatocellular carcinoma (HCC) is one of the major contributors to cancer burden worldwide, and its incidence has increased in recent decades. N6-methyladenosine (m6A) modification plays an important role in the tumorigenesis and metastasis of HCC by changing gene expression and function at multiple levels, such as ribonucleic acid (RNA) splicing, stability, translocation and translation. Methods The ONCOMINE, UALCAN, GEPIA, Kaplan–Meier plotter, cBioPortal for Cancer Genomics, STRING and TIMER2 databases were used for bioinformatic analyses. Quantitative polymerase chain reaction and western blotting were used to detect the expression of m6A RNA methylation regulators in HCC tissues. Results The transcription of m6A RNA methylation regulators was upregulated in patients with HCC, and overexpression of YTHDF1/2, YTHDC1, RBM15 and METTL3 was significantly correlated with clinical stages of HCC. In addition, downregulation of ZC3H13 and METTL14 and upregulation of other m6A RNA methylation regulators were associated with a poor prognosis. A high mutation rate (89%) of m6A RNA methylation regulators was also observed in patients with HCC, and mutations in methylation regulators were associated with poor overall survival and disease-free survival. Finally, the expression of the YTHDF family was significantly associated with immune infiltration in the HCC microenvironment. Conclusion m6A RNA methylation regulators and programmed death-ligand 1 may play an important role in the tumorigenesis and immune invasion and escape of HCC and may be risk factors affecting the survival of patients with HCC.