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Chronic alcohol\u2010induced metabolic stress impairs Fe\u2013S cluster stability and biosynthesis via reactive oxygen species (ROS)\u2010mediated oxidative damage and direct acetaldehyde toxicity, culminating in functional failure of this core cofactor. Current evidence is synthesized herein to delineate the hierarchical pathogenic cascade triggered by Fe\u2013S cluster dysfunction. At the cellular level, Fe\u2013S cluster depletion inactivates aconitase, driving citrate accumulation and redirecting carbon flux toward lipogenesis; concurrently, succinate dehydrogenase dysfunction causes succinate buildup, which epigenetically suppresses fatty acid oxidation. Impaired tRNA thiolation further compromises mitochondrial translational fidelity. Together, these defects precipitate an energy crisis and a self\u2010perpetuating lipotoxicity\u2013oxidative stress vicious cycle. At the systemic level, this metabolic dysregulation fuels disease progression from fatty liver and hyperlipidemia to atherosclerosis, mediated by enhanced hepatic VLDL secretion, reduced HDL levels, and oxidized LDL (Ox\u2010LDL) formation. Furthermore, a hypothetical structural model for acetaldehyde\u2010driven Fe\u2013S cluster disintegration, grounded in organometallic chemistry principles. Collectively, this review highlights the central role of Fe\u2013S clusters in alcohol\u2010associated metabolic disorders and provides a novel theoretical framework for developing therapeutics targeting Fe\u2013S cluster homeostasis.<\/jats:p>","DOI":"10.1002\/jbt.71082","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:01:50Z","timestamp":1786978910000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Iron\u2010Sulfur Cluster Targeting: A Novel Perspective for Treating Alcohol\u2010Related Lipid Metabolic Diseases"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1246-5216","authenticated-orcid":false,"given":"Li","family":"Xu","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences &amp; School of Public Health, Faculty of Medicine, Yangzhou University Yangzhou PR China"},{"name":"Key Laboratory of the Jiangsu Higher Education Institutions for Integrated Traditional Chinese and Western Medicine in Senile Diseases Control (Yangzhou University) Yangzhou PR China"},{"name":"Hangzhou Tangji Medical Technology Co. 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