Search Results (1,193)

Non-alcoholic fatty liver disease (NAFLD) affects one-quarter of the global population. The disease may progress from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. Unfortunately, lifestyle interventions and pharmacotherapies provide limited benefits to NAFLD patients. This systematic review which was conducted according to PRISMA 2020 guidelines, study selection, and data extraction, evaluated preclinical studies published between 1 January 2021 and 4 April 2026 that investigated liposome-based nanocarriers for NAFLD/NASH. Out of 477 records identified, 19 studies met the eligibility criteria and were included in the review. The included studies demonstrated that liposomal formulations prepared using thin-film hydration exhibited characteristics such as particle sizes of 80–160 nm, low polydispersity, zeta potentials of −55 to +35 mV (depending on surface modification), encapsulation efficiencies exceeding 75%, and sustained biphasic release profiles. Mechanistically, these nanocarriers targeted pathways by suppressing de novo lipogenesis through inhibition of FASN and SREBP-1c, enhancement of fatty acid oxidation through activation of AMPK signaling, mitigation of oxidative stress through Nrf2-mediated antioxidant responses, suppression of inflammation via NF-κB and TLR4 signaling, and attenuation of hepatic fibrosis via inhibition of the TGF-β/Smad pathway. Selected formulations also achieved adipose tissue targeting, thereby highlighting their potential to modulate liver–adipose tissue metabolic crosstalk. Despite these promising preclinical findings, clinical translation remains limited by methodological heterogeneity, inconsistent stability assessment, insufficient safety data, absence of clinical trials, biological barriers such as rapid mononuclear phagocyte system clearance, protein corona formation, and restricted penetration through the fibrotic extracellular matrix. Moreover, there are challenges in large-scale manufacturing and batch-to-batch reproducibility. Thus, rigorous toxicological evaluation and well-designed clinical trials are essential for facilitating the clinical translation of liposomal nanomedicines for treatment of liver diseases. Full article

With the advent of the new definition, fatty liver disorders have been reframed into metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and the mixed phenotype referred to as MetALD (MASLD and increased alcohol intake). This change reflects the real-world clinical practice, where metabolic dysfunction and alcohol frequently coexist and synergize to increase risks of steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). While conventional non-invasive tests (NITs) remain the backbone of risk stratification, lipidomics and metabolomics can capture biological information on disease mechanisms and may improve early detection and prognosis. Here, we summarize the current evidence on circulating and tissue lipidomic and metabolomic signatures across MASLD, ALD and MetALD, discuss how the new definitions affect clinical risk assessment, and highlight recent studies which partially distinguish molecular fingerprints for mixed etiology disease. Full article

Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder that can progress to non-alcoholic steatohepatitis (NASH), in which lipotoxicity, oxidative stress, apoptosis, and impaired autophagy contribute to liver injury. 14-Deoxy-11,12-didehydroandrographolide (deAND), a bioactive diterpenoid from Andrographis paniculata, has shown anti-inflammatory and antioxidant activities, but its role in NASH-associated lipotoxicity remains unclear. This study investigated the protective effects and underlying mechanisms of deAND using palmitic acid (PA)-treated AML12 hepatocytes and a choline-deficient, L-amino acid-defined, high-fat-diet (CDAHFD)-induced mouse model of NASH. In AML12 cells, PA impaired autophagic flux and reduced the expression of the mitophagy-associated proteins PINK1 and Parkin and increased p62, LC3-II, reactive oxygen species production, and apoptotic signaling. deAND treatment restored autophagic flux and increased PINK1 and Parkin expression, enhanced antioxidant defense-related proteins, including HO-1, GCLM, and GPX2, and reduced oxidative stress and apoptosis. The protective effects of deAND were attenuated by autophagy inhibitors, supporting the involvement of autophagy regulation. In CDAHFD-fed mice, deAND reduced hepatic steatosis, inflammation, fibrosis, apoptosis, and autophagy dysregulation. These findings suggest that deAND alleviates lipotoxic liver injury by restoring autophagic homeostasis and reducing oxidative stress. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive inflammatory and fibrotic subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), and its treatment landscape is rapidly moving from nonspecific liver fat reduction towards mechanism-based drug positioning. Since 2024, resmetirom and semaglutide have received U.S. Food and Drug Administration accelerated approval for non-cirrhotic MASH with moderate-to-advanced fibrosis, while tirzepatide, survodutide, and fibroblast growth factor 21 analogues have shown biopsy-based phase 2 or 2b efficacy signals. This narrative review organises approved and emerging pharmacotherapies within a pathogenesis-informed three-axis framework: the weight-insulin resistance-substrate load axis, the intrahepatic lipid reprogramming axis, and the inflammation-fibrosis transition and multi-axis integration axis. We further grade evidence maturity from regulatory or phase 3 histological evidence to phase 2 biopsy-based evidence and earlier imaging- or biomarker-based signals. This framework is intended to support phenotype-sensitive treatment positioning rather than a fixed therapeutic sequence. In particular, weight-centred treatment should not be assumed to apply to all patients, including normal-weight or lean MASH. Overall, future MASH therapy will likely depend on matching drug mechanisms, fibrosis stage, cardiometabolic phenotype, and treatment goals. Full article

Metabolic dysfunction-associated steatohepatitis (MASH; formerly non-alcoholic steatohepatitis, NASH) is characterized by oxidative stress, inflammatory activation, hepatocellular injury, and progressive liver dysfunction. However, the global transcriptomic landscape underlying stress-induced hepatic injury remains incompletely understood. In this study, we employed a methionine–choline-deficient (MCD) diet-induced murine model to characterize the phenotypic and transcriptomic alterations associated with liver injury. Male C57BL/6J mice were fed either a control or MCD diet, and hepatotoxicity was assessed by survival analysis, body and liver weight measurements, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, histopathological examination, RNA sequencing, quantitative real-time PCR (qRT-PCR), and tumor necrosis factor-alpha (TNF-α) enzyme-linked immunosorbent assay (ELISA). MCD feeding markedly reduced survival and body weight while inducing hepatomegaly and significant elevations in serum ALT and AST, indicating severe hepatocellular injury. Histopathological analysis demonstrated hepatic steatosis, hepatocellular ballooning, and lobular inflammation without histological evidence of fibrosis. Transcriptomic profiling revealed extensive gene expression remodeling, characterized by activation of inflammatory pathways, enrichment of MAPK-related signaling, dysregulation of lipid metabolism, suppression of antioxidant defense systems, impairment of cytochrome P450-mediated detoxification, and upregulation of apoptosis-associated genes. qRT-PCR further validated the differential expression of representative genes involved in inflammatory signaling (Tlr4, Nfkb1, Nlrp3, and Casp1), MAPK signaling (Fos), xenobiotic metabolism (Cyp4f18), lipid metabolism (Apoa4 and Lpl), extracellular matrix remodeling (Mmp12), and oxidative stress responses (Sod1 and Gstp1). In addition, elevated serum TNF-α levels provided protein-level evidence supporting activation of the TLR4/NF-κB/TNF-α/NLRP3 inflammatory axis. Although fibrosis-associated transcriptional responses were detected, the absence of histological fibrosis suggests transcriptional priming of fibrogenic pathways rather than established fibrogenesis. Collectively, these findings provide a transcriptomic framework linking oxidative stress, impaired detoxification, inflammatory activation, and stress-responsive signaling to MCD-induced hepatic injury. The MCD model provides a valuable experimental platform for characterizing hepatic stress-response transcriptomes and for generating hypotheses that can subsequently be evaluated in environmentally relevant toxicological models. Nevertheless, caution should be exercised when extrapolating these findings to obesity-associated human MASLD, as the MCD model lacks key metabolic features of the human disease, including obesity and insulin resistance. Therefore, the present findings should be interpreted primarily as transcriptomic signatures of stress-induced hepatic injury rather than as a direct representation of the pathophysiological processes underlying human obesity-associated MASLD. Full article

Non-alcoholic fatty liver disease (NAFLD), now increasingly termed metabolic dysfunction-associated steatotic liver disease (MASLD), is a growing cause of chronic liver disease with limited treatment options. Glucagon-like peptide-1 (GLP-1) receptor agonists, approved for type 2 diabetes and obesity, possess metabolic effects that may render them suitable for treating NAFLD and metabolic dysfunction-associated steatohepatitis (MASH). To evaluate the therapeutic effects of GLP-1 receptor agonists in adults with NAFLD, non-alcoholic steatohepatitis (NASH), MASLD, or MASH. PubMed, Scopus, Embase, and the Cochrane Library were systematically searched using keywords related to NAFLD and GLP-1 receptor agonists. Given heterogeneity in populations, designs, and outcomes, findings were synthesized narratively. The review is registered with PROSPERO (CRD420261337353). Twelve studies met the inclusion criteria. The most consistent outcome was a reduction in hepatic fat, seen with semaglutide, liraglutide, dulaglutide, and beinaglutide. Improvements in liver enzymes, particularly alanine aminotransferase, were less consistent and best regarded as supportive rather than definitive evidence of histological improvement. Histological benefits were strongest for steatohepatitis resolution in non-cirrhotic MASH. Fibrosis findings were mixed, with the greatest benefit in F2–F3 MASH and limited improvement in established cirrhosis. GLP-1 receptor agonists were generally well tolerated, with gastrointestinal symptoms the most common adverse effects. GLP-1 receptor agonists show promising liver-related benefits in NAFLD and MASH, particularly in obesity, type 2 diabetes, or earlier-stage disease. Their effects on advanced fibrosis and long-term outcomes remain uncertain, warranting larger, longer-term studies. Full article

Background: Small intestine bacterial overgrowth (SIBO) is associated with steatohepatitis (SH) in subjects with metabolic-associated steatotic liver disease (MASLD). The impact of ileocecal valve (ICV) incontinence, a major cause of SIBO in patients with MASLD, remains unknown because of the unmet need for a non-X-ray-dependent diagnosis. Methods: Exploiting water as contrast medium and colonic irrigation via a hydro-colon machine (Clean Colon Srl, Monza, Italy), we developed a new abdominal ultrasound (US) procedure for diagnosing and grading ICV incontinence. In a pilot, observational, feasibility and safety study, we correlated a new ICV incontinence parameter with irritable bowel syndrome (IBS, ROMA IV criteria), serum transaminases (AST, ALT), platelet counts, FIB-4, US liver steatosis and stiffness (LS, measured by Shear Wave and Transient Elastography, SWE and TE). Results: We prospectively studied 32 consecutive subjects with IBS who underwent a pre-colonoscopy colon cleansing after informed consent: 19 males (59%), body mass index (BMI) 26.6 ± 2.6 kg/m², age 57 ± 19 years, 16 (50%) with US liver steatosis. The half-hour (27 min, range 20–35 min) procedure was safe and well tolerated except in two males with prostate hypertrophy. ICV incontinence was graded (after 2500–3000 mL irrigation) according to cecum/right-colon distention with/without (immediate or delayed) reflux into terminal ileum (TI): 0 = cecum distension without TI reflux; 1 = cecum distension with TI reflux; 2 = absence of cecum distension with TI reflux. Cecum/right-colon distention (grade 0 or 1) was perceived by the patients whereas the right colon irrigation with complete ICV incontinence (grade 2) was symptomless. ICV continence associated with LS (p ≤ 0.0001). A histologic diagnosis of non-alcoholic steatohepatitis was confirmed in a 35-year-old obese male with SIBO and LS > 8 kPa (8.7/8.5 kPa by SWE/TE):steatosis (grade S3) with hepatocyte ballooning, lobular inflammation (grade 6/8) without fibrosis (stage 0/4, F0). Conclusions: The new US-based approach provides a feasible, easy-to-perform, mini-invasive tool for the diagnosis and grading of ICV incontinence. Preliminary results prompt prospective studies investigating the impact of ICV incontinence as a possible co-factor of steatohepatitis in patients with MASLD. Full article

Background: Clostridioides difficile infection (CDI) remains a leading cause of hospital-acquired infection. Metabolic-dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and has been associated with increased infectious susceptibility. However, whether non-cirrhotic MASLD independently worsens inpatient CDI outcomes and whether this differs across the MASLD spectrum remain unclear. Methods: We conducted a retrospective cohort study using the National Inpatient Sample (NIS) 2017–2023, identifying adult hospitalizations with a principal diagnosis of CDI. Patients with cirrhosis and alcoholic liver disease were excluded. Propensity score matching (1:1) was performed for the primary MASLD vs. non-MASLD comparison in the principal-diagnosis CDI cohort. To evaluate whether outcomes differ across the MASLD spectrum, survey-weighted multivariable logistic regression was used to compare K76.0-coded (MASLD without steatohepatitis) and K75.81-coded (MASH) hospitalizations against non-MASLD/MASH hospitalizations within the principal-diagnosis CDI cohort. The primary outcome was in-hospital mortality; secondary outcomes included complications, healthcare utilization, and discharge disposition. Results: The principal-diagnosis CDI cohort comprised 76,103 discharges (weighted ~380,515). MASLD prevalence among non-cirrhotic CDI hospitalizations nearly doubled from 1.98% in 2017 to 3.74% in 2023 (OR per year 1.089; p < 0.001). After propensity score matching (1756 pairs), MASLD was not associated with significantly higher in-hospital mortality (OR 1.252; p = 0.574) or most adverse outcomes, but was associated with lower odds of non-routine discharge (OR 0.794; p = 0.003). In the matched utilization analysis, length of stay and total charges were not significantly different, although the adjusted pre-match analysis showed higher charges among MASLD hospitalizations (+$4431; p = 0.001). Within the same principal-diagnosis cohort, K76.0-coded MASLD (n = 1988) was associated with lower odds of acute kidney injury (aOR 0.821; p = 0.004) and non-routine discharge (aOR 0.805; p = 0.001). K75.81-coded MASH (n = 197) was independently associated with higher in-hospital mortality (aOR 2.840, 95% CI 1.154–6.985; p = 0.023) and peritonitis (aOR 4.136, 95% CI 1.543–11.082; p = 0.005), although confidence intervals were wide and the number of MASH-coded hospitalizations was modest. Conclusions: The prevalence of MASLD among CDI hospitalizations is rising. Non-cirrhotic MASLD without steatohepatitis does not independently worsen inpatient CDI outcomes after adjustment, whereas K75.81-coded MASH may identify a higher-risk subgroup with increased mortality and peritonitis, pending confirmation in larger cohorts. These findings suggest that hepatic inflammatory activity, rather than steatosis alone, may drive adverse CDI outcomes and support further investigation of MASLD phenotyping in CDI risk stratification. Full article

Olfactory (or odorant) receptors (ORs) were initially characterized in 1991 by Drs. Richard Axel and Linda Buck, and subsequent additional efforts have contributed to our understanding of their canonical function in odorant identification in the nasal cavity, including ligands for many of the ORs and the signaling pathways involved. More recently, OR transcripts and proteins have been identified in cells and organs outside of the nasal cavity, ranging from skin to sperm to tumors, suggesting that they have biological roles in ectopic locations other than their canonical function of odorant molecule detection in the nose. This mini narrative review discusses ectopic human ORs and their potential ligand-activated functions in the skin, lung, and sperm, as well as in diseases such as nonalcoholic steatohepatitis (NASH), melanoma and prostate cancer. Full article

Background: Liver transplantation (LT) remains the definitive treatment for end-stage liver disease; however, post-LT outcomes may differ depending on underlying disease etiology. Our study aimed to compare post-LT outcomes between alcoholic and non-alcoholic steatohepatitis (NASH)-related liver transplant recipients in the United States. Methods: A retrospective cohort study was conducted using the TriNetX Research Network. Adult liver transplant recipients (≥18 years) were categorized into two mutually exclusive cohorts: alcoholic liver disease and NASH-related liver disease. Propensity score matching (1:1) was performed to balance baseline characteristics. Clinical outcomes were assessed. Comparative analyses included risk ratios, risk differences, odds ratios, Kaplan–Meier survival analysis, and hazard ratios with log-rank testing. Results: Compared with NASH recipients, alcoholic LT recipients had a significantly higher risk of rejection (14.5% vs. 12.1%; RR 1.195, 95% CI 1.076–1.327; p = 0.001) and hepatic encephalopathy (14.3% vs. 8.3%; RR 1.720, 95% CI 1.526–1.938; p < 0.001). Acute kidney injury was also more frequent in the alcoholic cohort (47.3% vs. 43.6%; RR 1.084, 95% CI 1.036–1.133; p < 0.001). In contrast, sepsis (15.6% vs. 18.0%; RR 0.869, 95% CI 0.794–0.952; p = 0.003) and CKD (46.1% vs. 51.1%; RR 0.901, 95% CI 0.863–0.939; p < 0.001) occurred less frequently in alcoholic LT patients. No significant differences were observed for liver transplant failure or ascites. Kaplan–Meier analyses demonstrated significantly lower rejection-free survival (HR 1.241, p < 0.001), higher hepatic encephalopathy (HR 1.808, p < 0.001), increased AKI risk (HR 1.150, p < 0.001) and higher all-cause mortality in the alcoholic cohort (HR 1.106, p = 0.031). Conclusions: In this large real-world matched cohort study, alcoholic LT recipients demonstrated higher risks of complications and all-cause mortality compared with NASH LT recipients. Full article

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver disease worldwide, affecting approximately 25% of the global population. MAFLD represents a broad disease spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The availability of experimental models that faithfully reproduce human metabolic and hepatic pathology is essential for elucidating disease mechanisms and advancing therapeutic development. This review aims to critically evaluate commonly used rodent models of MAFLD and provide guidance for model selection based on specific research objectives. Methods: A narrative, semi-systematic literature search was performed using PubMed Central, Ovid MEDLINE, and Google Scholar. Rodent models were classified according to their mode of disease induction, including diet-induced, genetically engineered, chemically or pharmacologically induced, and combination models. Models were assessed based on frequency of use, relevance to different stages of MAFLD progression, metabolic fidelity, and suitability for mechanistic studies and preclinical therapeutic evaluation. Results: Diet-induced models incorporating high fat, fructose, and cholesterol most closely recapitulate human metabolic dysfunction and are highly relevant for translational research and drug screening. Nutrient-deficient diets induce rapid steatohepatitis and fibrosis but lack key features of metabolic syndrome. Genetic models enable the targeted interrogation of specific metabolic and inflammatory pathways, whereas chemical and combination models accelerate fibrosis and HCC development. No single rodent model fully reproduces the entire spectrum of human MAFLD. Conclusions: Rodent models remain indispensable tools for MAFLD research; however, their applicability depends on alignment with the defined experimental goals. Careful selection of models based on disease stage, dominant pathogenic mechanisms, and translational intent is essential for improving reproducibility and clinical relevance. This review provides a practical framework to guide investigators in choosing appropriate preclinical models for mechanistic studies and therapeutic development in MAFLD. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of global chronic liver disease, with a prevalence of approximately 30%. This review outlines the diagnostic transition from the exclusionary non-alcoholic fatty liver disease (NAFLD) framework to the affirmative MASLD nomenclature, which mandates the presence of at least one of five specific cardiometabolic risk factors (CMRFs) to prioritize active pathophysiology. Beyond hepatic complications, MASLD drives systemic metabolic failure, significantly elevating risks for type 2 diabetes, hepatocellular carcinoma, and cardiovascular disease, the primary cause of mortality in this cohort. Clinical management relies on a standardized, two-tier risk-stratification pathway for advanced fibrosis. Primary care triage utilizes the Fibrosis–4 (FIB–4) index; a score < 1.3 excludes advanced disease via a high negative predictive value, whereas indeterminate or high scores require secondary validation via vibration-controlled transient elastography (VCTE) or the enhanced liver fibrosis (ELF) test to guide specialist referral. Although lifestyle modifications, principally a 7–10% weight reduction and Mediterranean diet adherence, remain foundational, management has transitioned toward disease-modifying pharmacotherapies. A pivotal breakthrough occurred with the 2024 FDA approval of resmetirom, a selective thyroid hormone receptor-beta (THR-β) agonist, for non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-advanced fibrosis. Concurrently, the emergence of GLP-1 receptor agonists and multi-incretin mimetics offers a personalized, multi-target approach simultaneously addressing hepatic inflammation, glycemic control, and adiposity. Full article

Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH) is frequently accompanied by disturbances in coagulation and metabolic homeostasis, partly related to impaired handling of vitamin K-dependent pathways. Although vitamin K is often administered to correct abnormal coagulation tests, its biochemical impact in hospitalized patients with MASH remains insufficiently characterized. This study aimed to evaluate changes in coagulation and metabolic parameters in hospitalized patients with MASH receiving vitamin K supplementation. Methods: We conducted a retrospective study of 84 hospitalized MASH patients who received vitamin K supplementation. Biochemical parameters were recorded at admission and discharge to assess short-term changes during hospitalization. Results: Vitamin K supplementation was associated with modest changes in coagulation parameters, including reductions in PT, INR, and aPTT (e.g., PT decreased from 13.00 s to 11.00 s). Small numerical changes in transaminases, fasting glucose, and total cholesterol were observed during hospitalization, with limited clinical relevance. These patterns were comparable across fibrosis stages, with no significant differences between groups. Discussion: The observed biochemical findings are likely in-hospital factors rather than a direct metabolic effect of vitamin K. Conclusions: Vitamin K supplementation was associated with modest changes in coagulation parameters and small, clinically negligible variations in selected metabolic markers in patients with MASH, irrespective of fibrosis stage. These findings suggest a supportive biochemical effect in selected contexts; further prospective studies are needed to clarify their clinical relevance. Full article

Background/Objectives: Non-alcoholic steatohepatitis (NASH) represents a worldwide health challenge with limited currently available effective treatment. The present analysis was designed to examine possible therapeutic advances of Ambrisentan (AMB) targeting multiple features of hepatic damage in dexamethasone (DEXA)-provoked nonalcoholic steatohepatitis (NASH) in rats. Methods: Rats were randomly divided into four groups: a control group; a DEXA group; and two AMB-treated groups that received AMB (5 or 10 mg/kg/day orally for a week) before and concomitantly with DEXA (8 mg/kg/day, i.p.) for 6 days. After completion of the experiment, serum markers of liver function and lipid profile were assessed, and hepatic histopathological alterations were examined. Results: AMB (mainly at 10 mg/kg/day) markedly ameliorated liver-function parameters, the lipid profile, and hepatic histopathological characteristics in DEXA-treated rats. MDA was reduced, whereas GSH, GPX4 and Nrf2 were heightened, indicating elevated oxidative damage. Moreover, AMB efficiently reinstated iron homeostasis and aggravated iron overload by altering serum iron, hepatic ferritin, transferrin and hepcidin. AMB decreased serum calcium and hepatic calcineurin A levels, followed by a reduction in hepatic autophagy biomarker Beclin-1. AMB downregulated pro-inflammatory biomarkers NF-κB, IL-6 and TGF-β1. Moreover, it notably repressed the hepatic gene expression of ferritinophagy biomarker NCOA4, with elevated FTH1 hepatic gene expression. Moreover, AMB ameliorated DEXA-induced changes in endothelial and vascular function by increasing hepatic PGI2 and cGMP and lowering ET-1 and iNOS. Conclusions: AMB improved DEXA-induced NASH, primarily through its action on endothelin pathways, with associated reductions in inflammation and the downstream processes of ferroptosis, ferritinophagy, lipophagy, and autophagy. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as key drivers of hepatocellular carcinoma (HCC). Unlike HCC caused by viral infections or alcohol, MASLD/MASH-related liver cancer develops within a chronic immunometabolic environment characterized by lipotoxicity, sterile inflammation, fibrogenesis, and remodeling of the microenvironment. In this setting, interleukin-10 (IL-10) has attracted growing attention due to its complex, context-dependent roles in immune regulation and tumor immune tolerance. This review explores IL-10 biology and its connection to MASLD/MASH-associated HCC, emphasizing the paradox that IL-10 may diminish harmful inflammation in early stages while promoting immunosuppressive conditions in advanced disease. To supplement existing research, we performed an exploratory reanalysis of publicly available bulk liver RNA-seq data from a mouse model that progresses from MASLD/MASH to HCC. The reanalysis revealed a receptor- and effector-specific rewiring of the IL-10 pathway: while the expression of canonical signaling genes (Stat3, Jak1, Jak2, Tyk2, Socs3) showed minimal changes across stages, receptor subunits (Il10ra, Il10rb) and IL-10-responsive effectors (such as Scd2, related to lipid metabolism, and Ddit4, involved in mTOR and glycolysis regulation) displayed strong stage-dependent induction. This was accompanied by a decrease in hepatocyte signature profiles and an increase in stromal and immune signatures. These results generate new hypotheses and raise key questions—particularly whether a large portion of IL-10 modulation originates from peripheral or non-parenchymal sources, and whether the transcriptional patterns observed reflect protein-level changes—that will require stage-specific, cell-focused human studies incorporating proteomic and cytokine measurements. Full article