Kim, Dong-Ho Kim, Mi-Jin Kim, Na-Young Lee, Seunghyeong Byun, Jun-Kyu Yun, Jae Won Lee, Jaebon Jin, Jonghwa Kim, Jina Chin, Jungwook Cho, Sung Jin Lee, In-Kyu Choi, Yeon-Kyung Park, Keun-Gyu 2024-01-19T10:33:57Z 2024-01-19T10:33:57Z 2023-02-17 2022-11 1976-6696 https://pubs.kist.re.kr/handle/201004/114280 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] English 생화학분자생물학회 DN200434, an orally available inverse agonist of estrogen-related receptor gamma, induces ferroptosis in sorafenib-resistant hepatocellular carcinoma Article 10.5483/BMBRep.2022.55.11.089 1 BMB Reports, v.55, no.11, pp.547 - 552 BMB Reports 55 11 547 552 Y scie scopus kci 000917912100005 2-s2.0-85142940282 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article DN200434 ERR? Ferroptosis Hepatocellular carcinoma Sorafenib