Targeting ferroptosis: Paving new roads for drug design and discovery

Ferroptosis, first proposed in 2012, is an iron-dependent form of regulated cell death characterized by excessive polyunsaturated fatty acid oxidation. In the past decade, researchers have revealed the formation and mechanisms of ferroptosis. Cancer drug resistance can be reversed by ferroptosis induction, and inhibiting ferroptosis has been shown to block certain disease processes. As a result, several ferroptosis-targeting drugs have been developed. However, the first-generation ferroptosis-targeting agents remain hampered from clinical use, mainly due to poor selectivity and pharmacokinetics. The discoveries of FSP1, GCH1, and other potential ferroptosis-regulating pathways independent of Xc(-)-GSH-GPX4 provide novel targets for drug design. Recently, protein-targeted degradation and antibody-drug conjugate strategy show promise in future drug design. With novel targets, further optimizations, and new technologies, the next-generation ferroptosis-targeting agents show a promising future with improved selectivity and efficacy. In this review, we summarize mechanisms, target types, drug design, and novel technologies of ferroptosis, aiming to pave the way for future drug design and discovery in the next decade.