{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:55:26Z","timestamp":1791435326969,"version":"4.3.3"},"reference-count":57,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T00:00:00Z","timestamp":1730160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Talent Plan of Jiangxi Province of China","award":["jxsq2023101080"],"award-info":[{"award-number":["jxsq2023101080"]}]},{"name":"Talent Plan of Jiangxi Province of China","award":["32370829"],"award-info":[{"award-number":["32370829"]}]},{"name":"Talent Plan of Jiangxi Province of China","award":["82360516"],"award-info":[{"award-number":["82360516"]}]},{"name":"Talent Plan of Jiangxi Province of China","award":["20224ACB216010"],"award-info":[{"award-number":["20224ACB216010"]}]},{"name":"National Natural Science Foundation of China","award":["jxsq2023101080"],"award-info":[{"award-number":["jxsq2023101080"]}]},{"name":"National Natural Science Foundation of China","award":["32370829"],"award-info":[{"award-number":["32370829"]}]},{"name":"National Natural Science Foundation of China","award":["82360516"],"award-info":[{"award-number":["82360516"]}]},{"name":"National Natural Science Foundation of China","award":["20224ACB216010"],"award-info":[{"award-number":["20224ACB216010"]}]},{"name":"Outstanding Youth Fund of Jiangxi Province","award":["jxsq2023101080"],"award-info":[{"award-number":["jxsq2023101080"]}]},{"name":"Outstanding Youth Fund of Jiangxi Province","award":["32370829"],"award-info":[{"award-number":["32370829"]}]},{"name":"Outstanding Youth Fund of Jiangxi Province","award":["82360516"],"award-info":[{"award-number":["82360516"]}]},{"name":"Outstanding Youth Fund of Jiangxi Province","award":["20224ACB216010"],"award-info":[{"award-number":["20224ACB216010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The crosstalk between tumor progression and ferroptosis is largely unknown. Here, we identify malate dehydrogenase 2 (MDH2) as a key regulator of ferroptosis. MDH2 deficiency inhibits the growth of hepatocellular carcinoma (HCC) cells and enhances their sensitivity to ferroptosis induced by RAS-selective lethal 3 (RSL3), a compound known to cause ferroptosis. MDH2 knock-down enhances RSL3-induced intracellular reactive oxygen species, free iron ions and lipid per-oxides levels, leading to HCC ferroptotic cell death which is rescued by ferrostatin-1 and iron chelator deferiprone. Importantly, the inhibition of HCC cell growth caused by MDH2 deficiency is partially rescued by ferroptosis blockade. Mechanistically, MDH2 resists RSL3-induced ferroptosis sensitivity dependent on glutathione peroxidase 4 (GPX4), an enzyme responsible for scavenging lipid peroxides, which is stabilized by MDH2 in HCC. The protein expressions of MDH2 and GPX4 are positively correlated with each other in HCC cell lines. Furthermore, through our UALCAN website analysis, we found that MDH2 and GPX4 are highly expressed in HCC samples. These findings reveal a critical mechanism by which HCC evades ferroptosis via MDH2-mediated stabilization of GPX4 to promote tumor progression and underscore the potential of MDH2 inhibition in combi-nation with ferroptosis inducers for the treatment of HCC.<\/jats:p>","DOI":"10.3390\/ijms252111604","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T08:42:09Z","timestamp":1730191329000},"page":"11604","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["MDH2 Promotes Hepatocellular Carcinoma Growth Through Ferroptosis Evasion via Stabilizing GPX4"],"prefix":"10.3390","volume":"25","author":[{"given":"Wenjia","family":"Yu","sequence":"first","affiliation":[{"name":"The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingping","family":"Li","sequence":"additional","affiliation":[{"name":"Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengchang","family":"Gao","sequence":"additional","affiliation":[{"name":"The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donglin","family":"Li","sequence":"additional","affiliation":[{"name":"The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangjie","family":"Chen","sequence":"additional","affiliation":[{"name":"The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0158-1164","authenticated-orcid":false,"given":"Bolei","family":"Dai","sequence":"additional","affiliation":[{"name":"The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoying","family":"Yang","sequence":"additional","affiliation":[{"name":"The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linfen","family":"Han","sequence":"additional","affiliation":[{"name":"The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8626-4291","authenticated-orcid":false,"given":"Qinqin","family":"Deng","sequence":"additional","affiliation":[{"name":"The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9940-8396","authenticated-orcid":false,"given":"Xueli","family":"Bian","sequence":"additional","affiliation":[{"name":"The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102765","DOI":"10.1016\/j.eclinm.2024.102765","article-title":"Worldwide burden of liver cancer across childhood and adolescence, 2000\u20132021: A systematic analysis of the Global Burden of Disease Study 2021","volume":"75","author":"Wu","year":"2024","journal-title":"eClinicalMedicine"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Abboud, Y., Shah, V.P., Bebawy, M., Al-Khazraji, A., Hajifathalian, K., and Gaglio, P.J. 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