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Alterations in systemic and hepatic metabolic pathways\u2014including insulin signaling, lipid metabolism, mitochondrial bioenergetics, and redox homeostasis\u2014reduce hepatic resilience to alcohol exposure and accelerate liver disease progression. Objective: This narrative review aims to integrate clinical, epidemiological, and mechanistic evidence published over the past two decades to examine how modifiable lifestyle factors contribute to metabolic reprogramming linking metabolic syndrome and alcohol-related liver disease with prioritization of high-level clinical evidence (cohort studies, meta-analyses, and guidelines). Key Findings: Modifiable lifestyle exposures such as alcohol consumption, cigarette smoking, unhealthy dietary patterns, and physical inactivity converge on common metabolically mediated pathways, including insulin resistance, dysregulated lipid metabolism and lipotoxicity, mitochondrial dysfunction, oxidative stress, chronic low-grade inflammation, and gut\u2013liver axis perturbations. These processes are reflected in altered metabolite profiles involving lipid species, bile acids, tricarboxylic acid cycle intermediates, and microbiota-derived metabolites, shaping a metabolic\u2013hepatic continuum. Among these, alcohol consumption and metabolic dysfunction show the strongest and most consistent associations with liver disease progression, with evidence supporting synergistic rather than additive effects. Conclusions: The coexistence of metabolic dysfunction and alcohol exposure is consistently associated with synergistic worsening of liver-related outcomes, including fibrosis progression, cirrhosis, and hepatocellular carcinoma. Recognition of metabolic alcohol-related liver disease (MetALD) underscores the need for integrated lifestyle-based strategies targeting alcohol consumption, smoking cessation, dietary quality, and physical activity to modulate shared metabolic and inflammatory pathways. A metabolically informed, systems-level approach may improve risk stratification, prevention, and management across the metabolic\u2013hepatic continuum.<\/jats:p>","DOI":"10.3390\/metabo16040224","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T12:11:44Z","timestamp":1774872704000},"page":"224","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Metabolic Reprogramming Driven by Modifiable Lifestyle Factors in Metabolic Syndrome and Alcohol-Related Liver Disease: A Narrative Review"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9597-3766","authenticated-orcid":false,"given":"Daniela","family":"Mih\u0103il\u0103","sequence":"first","affiliation":[{"name":"Doctoral School of Medicine, Faculty of Medicine, \u201cLucian Blaga\u201d University of Sibiu, 550024 Sibiu, Romania"},{"name":"Department of Internal Medicine, \u201cDr. Alexandru Augustin\u201d Military Clinical Emergency Hospital Sibiu, 550024 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hora\u021biu-Paul","family":"Domnariu","sequence":"additional","affiliation":[{"name":"Surgical Clinical Department, Faculty of Medicine, \u201cLucian Blaga\u201d University of Sibiu, 550024 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6258-633X","authenticated-orcid":false,"given":"Doru-Florian-Cornel","family":"Moga","sequence":"additional","affiliation":[{"name":"Surgical Clinical Department, Faculty of Medicine, \u201cLucian Blaga\u201d University of Sibiu, 550024 Sibiu, Romania"},{"name":"Clinical Department of Surgery, \u201cDr. Alexandru Augustin\u201d Military Clinical Emergency Hospital Sibiu, 550024 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7098-5525","authenticated-orcid":false,"given":"Carmen-Daniela","family":"Domnariu","sequence":"additional","affiliation":[{"name":"Department of Dental Medicine and Nursing, Faculty of Medicine, \u201cLucian Blaga\u201d University of Sibiu, 550024 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.7570\/jomes23052","article-title":"Metabolic dysfunction-associated steatotic liver disease","volume":"32","author":"Chan","year":"2023","journal-title":"J. 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