(1) Background: Ferroptosis is an apoptosis-independent cell death program implicated in many diseases including cancer. Emerging evidence suggests ferroptosis as a promising avenue for cancer therapy, but the paucity of mechanistic understanding of ferroptosis regulation and lack of biomarkers for sensitivity to ferroptosis inducers have significantly hampered the utility of ferroptosis-based therapy. (2) Methods: We performed integrated dataset analysis by correlating the sensitivity of small-molecule compounds (n = 481) against the transcriptomes of solid cancer cell lines (n = 659) to identify drug candidates with the potential to induce ferroptosis. Generalizable gene signatures of ferroptosis sensitivity and resistance are defined by interrogating drug effects of ferroptosis inducers (n = 7) with transcriptomic data of pan-solid cancer cells. (3) Results: We report, for the first time, the comprehensive identification of drug compounds that induce ferroptosis and the delineation of generalizable gene signatures of pro- and anti-ferroptosis in pan-cancer. We further reveal that small cell lung cancer (SCLC) and isocitrate dehydrogenase (IDH1/2)-mutant brain tumors show enrichment of pro-ferroptosis gene signature, suggesting a unique vulnerability of SCLC and IDH-mutant tumors to ferroptosis inducers. Finally, we demonstrate that targeting class I histone deacetylase (HDAC) significantly enhances ferroptotic cell death caused by Erastin, an ferroptosis inducer, in lung cancer cells, revealing a previously underappreciated role for HDAC in ferroptosis regulation. (4) Conclusions: Our work reveals novel drug compounds and gene networks that regulate ferroptosis in cancer, which sheds light on the mechanisms of ferroptosis and may facilitate biomarker-guided stratification for ferroptosis-based therapy.
