Ferroptosis, closely linked to the pathogenesis and progression of numerous diseases, has emerged as a significant frontier in drug discovery. FSP1, a key regulator of lipid peroxidation acting in parallel with GPX4, represents a promising therapeutic target for ferroptosis modulation. In this study, we designed and synthesized two distinct classes of PROTAC degraders based on the FSP1 inhibitor iFSP1. Through activity screening, the lead compound 2307 demonstrated potent FSP1 degradation activity via the ubiquitin-proteasome system, achieving a DC50 value of 263.7 nM without exhibiting a hook effect. Flow cytometry and confocal microscopy experiments confirmed that 2307 significantly induces the accumulation of intracellular lipid peroxides. Furthermore, 2307 exhibits moderate antiproliferative effects, and cellular assays established its synergistic induction of ferroptosis with GPX4 inhibitors. Notably, treatment with 2307 upregulated the mRNA expression of ferroptosis-related proteins. Collectively, compound 2307 serves as a valuable tool compound for investigating ferroptosis mechanisms and advancing its therapeutic applications in drug development.
