Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) progresses from hepatic steatosis to hepatocellular carcinoma (HCC) as a result of systemic immunometabolic dysfunction. This review summarizes the key roles of the innate and adaptive immune mechanisms driving hepatic injury, fibrogenesis, and carcinogenesis in MASLD. Methods: A comprehensive literature review was performed using PubMed to identify relevant published studies. Eligible articles included original research and clinical studies addressing immunological and metabolic mechanisms in MASLD, as well as emerging therapeutic strategies. Results: We highlight the roles of cytokine networks, the gut–liver axis, and immune cell reprogramming. Emerging therapeutic strategies, including cytokine inhibitors, anti-fibrotic agents, metabolic modulators, and nutraceuticals, offer several indications for attenuating MASLD progression and reducing the prevalence of extrahepatic manifestations. Conclusions: Given the heterogeneity of MASLD, personalized combination-based approaches targeting both inflammation and metabolic stress are essential for effective disease management and the prevention of systemic complications.

Alcohol-associated liver disease (ALD) includes a spectrum from steatosis and steatohepatitis to cirrhosis and hepatocellular carcinoma driven by oxidative stress, immune activation, and systemic inflammation. Ethanol metabolism through alcohol dehydrogenase, aldehyde dehydrogenase, and cytochrome P450 2E1 generates reactive oxygen and nitrogen species, leading to mitochondrial dysfunction, hepatocellular injury, and activation of inflammatory and fibrogenic pathways. Beyond hepatic effects, ALD engages the gut–liver–brain axis, where microbial dysbiosis, blood–brain barrier disruption, and neuroinflammation contribute to cognitive impairment and cerebrovascular risk. The emerging concept, metabolic dysfunction-associated steatotic liver disease and increased alcohol intake (MetALD), presents the synergistic impact of alcohol and metabolic comorbidities, enhancing oxidative injury and fibrosis. This review summarizes key mechanisms connecting oxidative stress to multisystem pathology and highlights the need for precision therapies targeting redox imbalance, immune dysregulation, and gut–brain–liver interactions to improve outcomes in ALD and MetALD.

Chronic alcohol consumption induces oxidative stress not only in the liver but also in the gastrointestinal tract, where prolonged intestinal ethanol absorption plays a pivotal and underrecognized role. This review reframes ethanol pharmacokinetics to emphasize sustained jejunal and ileal uptake, which maintains elevated blood alcohol levels and perpetuates redox imbalance across the gut–liver axis. We integrate recent findings on ethanol-induced barrier dysfunction, CYP2E1-mediated ROS production, microbial dysbiosis, and mitochondrial disruption, proposing that the intestine is an active site of injury and a driver of systemic inflammation. Key mechanistic insights reveal that gut-derived endotoxins, compromised epithelial integrity, and microbiome–mitochondria interactions converge to exacerbate hepatic and extrahepatic damage. We further explore emerging therapeutic strategies—ranging from NAD⁺ repletion and probiotics to fecal microbiota transplantation—that target this upstream pathology. Recognizing prolonged intestinal ethanol absorption as a clinically meaningful phase offers new directions for early intervention and redox-based treatment in alcohol-associated disease.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is an increasingly prevalent liver disorder. Objectives: This study investigated the effect of smoking status on various clinical outcomes in MASLD and metabolic dysfunction and alcohol-associated liver disease (MetALD). Design: This study is a retrospective cohort analysis utilizing data from the UK Biobank (Application ID: 117214). Participants were categorized as current, previous, or never smokers, and outcomes were analyzed using inverse probability of treatment weighting to adjust for confounders. Methods: The primary outcomes were all-cause mortality and liver-related mortality. Secondary outcomes included incidence of liver cirrhosis, hepatic decompensation, cardio-cerebrovascular diseases (CVD), and hepatocellular carcinoma (HCC). Multivariate Cox proportional hazards models were employed to evaluate associations. Results: Previous and never smokers had significantly lower hazard ratios (HRs) for mortality compared to current smokers in all cohorts (HR: 0.33, 95% confidence interval (CI): 0.31–0.35, p < 0.001 for never smokers in No SLD cohort, HR: 0.43, 95% CI: 0.41–0.44, p < 0.001 for never smokers in MASLD cohort, and HR: 0.41, 95% CI: 0.38–0.45, p < 0.001 for never smokers in MetALD cohort). Previous and never smokers showed significantly lower incidences of liver cirrhosis compared to current smokers across all cohorts, except for MetALD. Previous and never smokers showed lower incidences of CVD compared to current smokers. In the MASLD cohort, never smokers had the lowest incidence of hepatic decompensation and HCC. In the MetALD cohort, no significant differences were observed in the risk of hepatic decompensation and HCC between different smoking statuses. Conclusion: Smoking is related to worse survival outcomes and higher incidences of liver cirrhosis and CVD in MASLD and MetALD cohorts. Therefore, smoking cessation and prevention are crucial strategies for reducing the burden of liver disease and improving patient prognosis.

Alcohol-associated liver disease (ALD) has become a major global concern, but the development of effective drugs remains a challenge despite numerous preclinical and clinical pieces of research on the effects of natural compounds. To address this, a meta-analysis was conducted on the efficacy of Panax ginseng for ALD based on preclinical studies. We identified 18 relevant studies from PubMed, Web of Science, and Cochrane Library database and evaluated their methodological quality using the Systematic Review Centre for Laboratory animal Experimentation tool. We analyzed the data using I², p-values, and fixed effects models to assess overall efficacy and heterogeneity. The results of the meta-analysis suggested that Panax ginseng treatment is effective in reducing the levels of inflammatory markers associated with hepatic injury caused by ALD in animal experiments. Additionally, the administration of Panax ginseng was found to down-regulate inflammatory cytokines and attenuate lipid metabolism in ALD. Moreover, Panax ginseng markedly improved the antioxidant systems in ALD. Therefore, we concluded that Panax ginseng has the potential to be a promising therapeutic agent for ALD. Further research is needed to confirm these findings and to determine the optimal dosage and duration of treatment for patients with ALD.

Coffee consumption is globally widespread and has become a lifestyle habit. This study investigated coffee consumption and liver-related survival in a large cohort of 455,870 individuals with UK biobank, categorized into without steatosis, metabolic dysfunction-associated steatotic liver disease (MASLD), and MASLD and increased alcohol intake (MetALD). Inverse probability of treatment weighting (IPTW) adjusted for confounding variables was used, followed by Kaplan–Meier analysis. Moderate coffee consumption (1–2 cups per day) was associated with lower all-cause mortality across the entire cohort, without the steatosis, MASLD (p < 0.0001), and MetALD cohorts (p = 0.0047 for pre-IPTW, p = 0.027 for post-IPTW). Before IPTW adjustment, consuming one or more cups of coffee per day appeared to significantly reduce liver-related mortality in the overall (p = 0.015) and MASLD cohorts (p = 0.011). However, post-IPTW application, no significant differences in liver-related mortality were observed between the coffee intake groups (p = 0.778, 0.319, 0.564, 0.238 for each group). While increased coffee consumption initially seemed to reduce liver-related mortality, after IPTW adjustment, only all-cause mortality significantly decreased (p < 0.0001 and p = 0.027). These findings suggest that previous studies might have overestimated the favorable effect of coffee intake on chronic liver disease due to confounding factors.