Ferroptosis in Human Disease: Molecular Circuitry, Cross-Disciplinary Regulatory Networks, and Novel Therapeutic Frontiers

Ferroptosis is a regulated form of cell death driven by iron-dependent phospholipid peroxidation. Since its formal description just over a decade ago, this process has emerged as a central link between fundamental cell biology and the pathophysiology of diverse clinical conditions, including cancer, neurodegeneration, ischemia–reperfusion injury, organ fibrosis, metabolic disorders, and infectious diseases. The molecular architecture of ferroptosis is centered on 4 interconnected axes: iron metabolism and labile iron pool dynamics; biosynthesis and oxidation of polyunsaturated fatty acid-containing phospholipids; the glutathione–glutathione peroxidase 4 reductive defense system; and parallel surveillance pathways, including the ferroptosis suppressor protein 1–coenzyme Q and GTP cyclohydrolase 1–tetrahydrobiopterin circuits. This review synthesizes the current mechanistic understanding of these networks, critically evaluates the pathophysiological roles of ferroptosis across major organ systems, and assesses the therapeutic landscape, which encompasses ferroptosis-inducing strategies for cancer and ferroptosis-inhibiting approaches for treating degenerative and ischemic diseases. We also discuss challenges to clinical translation, notably the absence of validated biomarkers, the context-dependent regulation of ferroptosis, and the need for tissue-selective pharmacological interventions. By integrating perspectives from cell biology, redox biochemistry, lipid metabolism, immunology, and pharmacology, this review provides a cross-disciplinary framework for understanding ferroptosis as both a fundamental biological process and a target for therapeutic intervention.