Jianni Qi

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease globally, and its high prevalence underscores the central role of metabolic dysregulation in its pathogenesis. Recent epidemiological studies have shown that MASLD is associated not only with hepatocellular carcinoma but also with an increased risk of several extrahepatic malignancies, including esophageal, gastric, colorectal, pancreatic, thyroid, breast, endometrial, renal, and prostate cancers. This review summarizes the emerging epidemiological links between MASLD and these extrahepatic cancers and discusses the biological mechanisms that may underlie these associations. We aim to describe both shared and organ-specific pathogenic pathways, highlight the importance of viewing MASLD as a systemic metabolic disorder in cancer prevention and clinical management, and outline future research directions from both conceptual and clinical perspectives. Future efforts should focus on biomarker development, multidisciplinary collaboration, and interventions targeting metabolic pathways.

Background: Gut microbiota-derived metabolites may contribute to liver fibrosis by affecting host inflammatory, metabolic, and epigenetic pathways. We aimed to identify microbiota-associated host genes shared across liver fibrosis of different etiologies. Methods: Microbiota- and metabolite-associated host genes were obtained from gutMGene v2.0 and integrated with differentially expressed genes from two human liver transcriptomic datasets: GSE84044 for HBV-related fibrosis and GSE49541 for NAFLD-related fibrosis. Shared genes were analyzed using protein–protein interaction and functional enrichment analyses. Selected metabolite–protein interactions were assessed by molecular docking and molecular dynamics simulations. Two-sample Mendelian randomization was used to examine potential associations between candidate gene expression and liver fibrosis risk. Results: Fourteen microbiota-associated genes were differentially expressed in both fibrosis cohorts, including CCL2, CCL20, CXCL6, PTGS2, HDAC2, HDAC3, ADRA2A, SOD1, PEMT, and GNMT. These genes were mainly associated with chemokine activity, histone deacetylation, and IL-17 and TNF signaling. Molecular docking suggested structural compatibility between phenylacetylglutamine and ADRA2A, while butyrate showed weaker predicted interactions with HDAC2 and HDAC3.Molecular dynamics analysis supported the stability of the ADRA2A–phenylacetylglutamine complex under the simulated conditions. Mendelian randomization identified nominal associations of HDAC3, CCL2, PTGS2, and VCL expression with liver fibrosis risk. Conclusions: This study identified shared microbiota-associated host regulatory candidates in HBV- and NAFLD-related liver fibrosis.HDAC3 and ADRA2A may represent potential links between microbial metabolic signals and fibrotic responses, although further experimental validation is required.

Background: Alcohol‐associated liver disease (ALD) is a major cause of advanced liver disease, with limited effective clinical interventions, highlighting an urgent need for new therapeutic targets. Acyl‐CoA:cholesterol acyltransferase 1 (ACAT1) is a key cholesterol‐metabolizing acyltransferase that catalyzes the esterification of free cholesterol into cholesteryl esters. It is highly expressed predominantly in macrophages and participates in the regulation of macrophage functions. Nevertheless, its role and underlying mechanism in alcoholic liver injury remain largely unclear. Results: We observed that co‐stimulation with ethanol and LPS up‐regulated ACAT1 expression, triggered inflammatory responses in macrophages, and aggravated liver function impairment, lipid deposition, and ROS accumulation in mice, thereby contributing to the progression of ALD. Mechanistically, ACAT1 upregulation induces mitochondrial damage and activates the NLRP3 inflammasome. Conclusion: ACAT1 is a positive regulatory factor in the inflammatory response of macrophages. It exacerbates ALD by inducing mitochondrial damage and activating NLRP3, providing a theoretical basis for the mechanism by which ACAT1 promotes ALD progression.

Hepatic fibrosis and cirrhosis represent an important pathological continuum in the progression of chronic liver disease to primary liver cancer and are as

Background: Hepatocyte nuclear factor 6 (HNF6), a member of the HNF family, contains single cleft and homologous domains, which form a DNA-binding region that targets the promoter regions of genes that bind to liver-specific genes and regulate their expression. Furthermore, HNF6 is highly expressed as an HNF in the liver. Main body: HNF6 regulates not only the formation of the liver but also the proliferation and differentiation of hepatocytes. Additionally, HNF6 controls the migration and adhesion of hepatocellular carcinoma cells and plays a significant role in liver metabolism. Its expression is affected by epigenetic modifications such as DNA methylation, post-translational modifications, and microRNAs. Recently, HNF6 was also found to be expressed in tissues, such as the pancreas, intestine, and lungs, where it controls their formation by regulating cell differentiation and influences their pathophysiological processes via various mechanisms. Conclusion: In this review, we highlight advances in HNF6-related research concerning liver diseases and provide a summary of its potential mechanisms of action as a transcription factor in regulating downstream genes and epigenetic modifications. We also highlight gaps in liver disease research and provide future research directions for the application of HNF6 and its downstream molecules as attractive targets in the treatment of liver diseases.