Small-molecule ferroptosis modulators in oncology: Design principles, evidence standards, and translational opportunities

Ferroptosis is an iron-dependent regulated cell-death process driven by toxic lipid peroxidation when antioxidant and lipid-quality-control defenses fail. In oncology, this process offers a route to exploit tumor states that evade apoptosis yet remain dependent on redox, lipid, iron, and organelle homeostasis, including mesenchymal, metastatic, therapy-refractory, stem-like, and drug-tolerant persister states. This Review argues that small-molecule ferroptosis modulators should be prioritized by threshold state, evidence standard, and therapeutic use case rather than by nominal ability to induce or suppress cell death. Here, ferroptosis pharmacology is organized around substrate pressure, suppressor capacity, protective lipid remodeling, neutral-lipid storage and turnover, iron-dependent radical propagation, targeted protein degradation, autophagy-linked regulation, radical-trapping rescue, hybrid design, and resistance-state deployment. The central medicinal-chemistry challenge is to align chemical structure, mechanism assignment, exposure, selectivity, pharmacodynamic lipid biology, and tumor-state context closely enough to support rational oncology development.