Iron‐Sulfur Cluster Targeting: A Novel Perspective for Treating Alcohol‐Related Lipid Metabolic Diseases

ABSTRACT

Iron–sulfur (Fe–S) clusters are pivotal molecular cofactors bridging inorganic chemistry and organic life processes, with their tightly regulated biosynthesis and function underpinning cellular metabolic homeostasis. Chronic alcohol‐induced metabolic stress impairs Fe–S cluster stability and biosynthesis via reactive oxygen species (ROS)‐mediated 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–S cluster dysfunction. At the cellular level, Fe–S 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‐perpetuating lipotoxicity–oxidative 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‐LDL) formation. Furthermore, a hypothetical structural model for acetaldehyde‐driven Fe–S cluster disintegration, grounded in organometallic chemistry principles. Collectively, this review highlights the central role of Fe–S clusters in alcohol‐associated metabolic disorders and provides a novel theoretical framework for developing therapeutics targeting Fe–S cluster homeostasis.