Histone demethylase KDM3B protects against ferroptosis by upregulating SLC7A11

Ferroptosis is a type of adaptive cell death driven by cellular metabolism and iron‐dependent lipid peroxidation. Though multiple genes (including SLC7A11 and GPX4) have been demonstrated to play key roles in ferroptosis, little is known about the epigenetic regulation of this process. Here, we report that KDM3B, a histone H3 lysine 9 demethylase, can protect against ferroptosis induced by Erastin, an inhibitor of SLC7A11. KDM3B overexpression in HT‐1080 cells results in decreased histone H3 lysine 9 methylation. Furthermore, KDM3B upregulates the expression of SLC7A11 through cooperation with the transcription factor ATF4. In summary, we identify here KDM3B as a potential epigenetic regulator of ferroptosis. KDM3B protects cells from Erastin‐induced ferroptosis through transcriptional upregulation of SLC7A11 via interaction with ATF4. Therefore, small molecule targeting of KDM3B can resensitize Erastin‐resistant cancer cells to ferroptosis induction and thus may have potential as a possible strategy to induce ferroptosis‐associated cancer cell death.