From Redox Vulnerability to Therapeutic Translation: Ferroptosis in Cancer Through Natural-Product Scaffolds, ‎Resistance Biology, and Precision Targeting ‎

Abstract

Abstract

Ferroptosis has emerged as a therapeutically exploitable form of regulated cell death governed by iron metabolism, phospholipid peroxidation, and redox homeostasis. Its ability to eliminate metabolically adapted and therapy-resistant cancer cells has generated substantial interest; however, clinical translation remains limited by redundant antioxidant defenses, tumor metabolic plasticity, insufficient biomarkers, and the frequent disconnect between in vitro ferroptotic phenotypes and in vivo efficacy. Natural products offer structurally diverse and pharmacologically versatile scaffolds capable of targeting these vulnerabilities, yet the mechanistic evidence supporting many proposed ferroptosis modulators remains inconsistent. This review critically integrates the molecular architecture of ferroptosis with cancer redox vulnerability, resistance mechanisms, and natural-product pharmacology. Particular emphasis is placed on the SLC7A11–GSH–GPX4 axis and GPX4-independent defense systems, including FSP1–CoQ10, DHODH–CoQH2, and GCH1–BH4, together with iron homeostasis, ferritinophagy, lipid remodeling, and NRF2-dependent adaptation. Rather than cataloguing compounds, natural products are evaluated according to chemical class, molecular target, tumor context, and strength of ferroptosis-specific evidence. Combination strategies, tumor-micro environmental determinants, precision delivery, computational discovery, biomarkers, and translational barriers are also critically examined. Finally, we propose an evidence hierarchy and translational roadmap that distinguish biochemical association from pharmacological rescue, mechanistic confirmation, in vivo validation, and clinically relevant evidence. By linking natural-product chemical diversity to ferroptosis dependency and resistance biology, this review defines key experimental priorities for translating ferroptosis into a pharmacologically actionable strategy in oncology.