DN200434, an orally available inverse agonist of estrogen-related receptor , induces ferroptosis in sorafenib-resistant hepatocellular carcinoma

Sorafenib, originally identified as an inhibitor of multiple onco-genic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear recep-tor estrogen-related receptor gamma (ERR gamma) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERR gamma with DN200434, an orally available inverse agonist, can over-come resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenib-induced ferroptosis and showed significantly higher ERR gamma levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Me-chanistically, DN200434 increased mitochondrial ROS genera-tion by reducing glutathione/glutathione disulfide levels, which sub-sequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results in-dicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib. [BMB Reports 2022; 55(11): 547-552]