Ferroptosis regulator families in metabolic diseases: Molecular networks and therapeutic opportunities.

Ferroptosis represents a metabolically wired cell-death program where iron-dependent lipid peroxidation intersects with oxidative stress, disordered lipid metabolism, and chronic inflammation, creating a permissive environment for metabolic disease progression. Metabolic stress creates a permissive landscape for ferroptosis through three convergent liabilities: enlargement of redox-active iron pools, membrane enrichment with polyunsaturated phospholipids, and constrained thiol-based detoxification capacity. Within this context, glutathione (GSH) peroxidases (GPX1, GPX3, GPX4), acyl-CoA synthetase long-chain (ACSL) family (ACSL1, ACSL4), and the cystine and GSH transporter solute carrier family 7 member 11 (SLC7A11) form a core ferroptosis regulatory axis that integrates lipid remodeling, antioxidant defense, and amino acid metabolism. Coordinated actions within this axis detoxify phospholipid hydroperoxides, regulate membrane lipid composition, and sustain cysteine and GSH availability, collectively establishing a metabolic checkpoint that determines ferroptosis sensitivity. Disruption of this checkpoint contributes to adipose dysfunction in obesity, beta-cell failure in diabetes, hepatocellular injury in fatty liver disease, myocardial and vascular injury in cardiovascular disease, and tubular damage in chronic kidney disease. Mitochondrial dysfunction, inflammatory signaling, and nutrient-sensing pathways further tune ferroptosis vulnerability in an organ- and stage-dependent manner. Therapeutic strategies that enhance GPX4 activity, inhibit ACSL4-driven lipid remodeling, or stabilize cysteine metabolism show promise in mitigating ferroptosis-driven organ injury and restoring metabolic homeostasis. This review conceptualizes ferroptosis through an integrated metabolic regulatory framework that reconciles diverse observations across metabolic diseases and highlights actionable targets for precision metabolic intervention.