Ferroptosis in Cancer and Inflammatory Diseases: Mechanisms and Therapeutic Implications

Abstract

Ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation, has emerged as a critical pathophysiological mechanism linking cancer and inflammatory diseases. The seemingly distinct pathologies exhibit shared microenvironmental hallmarks—oxidative stress, immune dysregulation, and metabolic reprogramming—that converge on ferroptosis regulation. This review synthesizes how ferroptosis operates at the intersection of these diseases, acting as both a tumor-suppressive mechanism and a driver of inflammatory tissue damage. In cancer, ferroptosis eliminates therapy-resistant cells but paradoxically facilitates metastasis through lipid peroxidation byproducts that remodel the tumor microenvironment and suppress antitumor immunity. In chronic inflammatory diseases—from atherosclerosis to rheumatoid arthritis—ferroptosis amplifies neuroinflammatory cascades while simultaneously exposing vulnerabilities for therapeutic targeting. Central to this duality are shared regulatory nodes, including nuclear factor kappa B-driven inflammation, NOD-like receptor family pyrin domain-containing 3 inflammasome activation, and GPX4 dysfunction. Therapeutically, ferroptosis induction shows promise against therapy-resistant cancers but risks exacerbating inflammatory damage, underscoring the need for precision modulation. Emerging strategies—nanoparticle-based inducers, immunotherapy combinations, and biomarker-guided patient stratification—aim to balance prodeath efficacy against off-target toxicity. By dissecting the ferroptosis–inflammation–cancer axis, this review provides a unified framework for understanding disease pathogenesis and advancing therapies for conditions resistant to conventional treatments. Future research must prioritize spatial mapping of ferroptosis dynamics, mechanistic crosstalk with immune checkpoints, and combinatorial regimens that exploit ferroptosis vulnerabilities while mitigating its inflammatory consequences.