Discovery of a Novel Benzimidazole Derivative Targeting Histone Deacetylase to Induce Ferroptosis and Trigger Immunogenic Cell Death

Ferroptosis is a unique type of cell death, characterized by its reliance on iron dependency and lipid peroxidation (LPO). Consequently, small-molecule ferroptosis modulators have garnered substantial interest as a promising avenue for cancer therapy. Herein, we explored the ferroptosis sensitivity of epigenetic modulators and found that the antiproliferative effects of class I histone deacetylase (HDAC) inhibitors are significantly reliant on ferroptosis. Subsequently, we developed a novel series of HDAC inhibitors, identifying <b>HL-5s</b> with robust inhibitory activity against class I HDACs, particularly HDAC1. Notably, <b>HL-5s</b> induces ferroptosis by augmenting LPO production. Mechanistically, <b>HL-5s</b> increased the YB-1 acetylation and inhibited the Nrf2/HO-1 signaling pathway. Furthermore, <b>HL-5s</b> not only significantly suppresses tumor growth in the PC-9 xenograft model but also remodels the tumor microenvironment in the LLC allograft model. Our study has unveiled that class I HDAC inhibitors can exert antitumor effects by triggering ferroptosis, and <b>HL-5s</b> may serve as a promising candidate for future cancer treatment.