ZK53 enhances tumor cell susceptibility to ferroptosis via ClpP-mediated mitochondrial dysfunction

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. This process has garnered increasing attention due to its potential as a promising therapeutic strategy for cancer. In this study, through functional screening, we identified ZK53, a small molecule that sensitizes cells to the ferroptosis inducer RSL3. Comprehensive functional characterization confirmed that ZK53 effectively enhances ferroptosis across multiple cell lines. Mechanistically, both knockdown and overexpression experiments demonstrated that ClpP, the target of ZK53, is a previously unrecognized pro-ferroptosis factor. Notably, ZK53 enhances ferroptosis via ClpP dependency and promotes cell death by inducing mitochondrial dysfunction. <i>In vivo</i>, ZK53 synergized with ferroptosis inducers IKE to significantly inhibit tumor growth in xenograft models by promoting ferroptosis. Taken together, our findings identify ClpP as a novel target for ferroptosis and suggest that ZK53 may serve as a promising candidate for enhancing ferroptosis-based cancer therapy.