{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:36:49Z","timestamp":1785411409595,"version":"3.56.0"},"reference-count":26,"publisher":"National Academy of Sciences","issue":"24","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017596","name":"Natural Science Basic Research Program of Shaanxi Province","doi-asserted-by":"crossref","award":["2024JC-YBQN-0891"],"award-info":[{"award-number":["2024JC-YBQN-0891"]}],"id":[{"id":"10.13039\/501100017596","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Centrally-Guided Local Special Project for the Development of Science and Technology Achievement Transfer and Commercialization","award":["Z2025-XCZX-0059"],"award-info":[{"award-number":["Z2025-XCZX-0059"]}]},{"name":"Xi\u2019an Science and Technology Program-Key Industrial Chain Technology Tackling Cluster Project","award":["25ZDLJQ00019"],"award-info":[{"award-number":["25ZDLJQ00019"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,16]]},"abstract":"<jats:p>Tumor hypoxia promotes dedifferentiation and metabolic reprogramming in hepatocellular carcinoma (HCC), undermining normal liver functions. Here, we identify the E3 ubiquitin ligase RNF126 as a hypoxia-inducible \u201cperoxisomal fate\u201d switch that links the hypoxic microenvironment to loss of hepatocyte differentiation. Under hypoxia, HIF-2\u03b1 drives RNF126 expression, which in turn ubiquitinates the peroxisomal membrane transporter ABCD3, triggering selective peroxisome autophagy (pexophagy) and depletion of peroxisomes. This organelle loss ablates very-long-chain fatty acid \u03b2-oxidation and hydrogen peroxide detoxification, erasing key hepatocyte differentiation features. We show that genetic RNF126 ablation restores peroxisomal functions and impairs hypoxic HCC growth. Leveraging these insights, we developed a small-molecule RNF126 inhibitor, D665-1412, which selectively blocks hypoxia-induced pexophagy. D665-1412 treatment stabilizes peroxisomes, normalizes lipid metabolism, and reactivates hepatocytic differentiation markers, thereby \u201credifferentiating\u201d HCC cells and suppressing tumor progression in vitro and in vivo. Our findings establish the HIF-2\u03b1\u2013RNF126\u2013ABCD3 axis as a driver of HCC dedifferentiation and present organelle-targeted redifferentiation therapy as a promising approach for liver cancer.<\/jats:p>","DOI":"10.1073\/pnas.2535777123","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T17:36:04Z","timestamp":1781026564000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["RNF126 is a peroxisomal fate switch enabling redifferentiation therapy in hepatocellular carcinoma"],"prefix":"10.1073","volume":"123","author":[{"given":"Qi","family":"Su","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zhmm22","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmacy, Health Science Center, Xi\u2019an Jiaotong University","place":["Xi\u2019an, PR China"]},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering","place":["Xi\u2019an, PR China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichun","family":"Yang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zhmm22","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmacy, Health Science Center, Xi\u2019an Jiaotong University","place":["Xi\u2019an, PR China"]},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering","place":["Xi\u2019an, PR China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayan","family":"Ren","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zhmm22","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmacy, Health Science Center, Xi\u2019an Jiaotong University","place":["Xi\u2019an, PR China"]},{"name":"State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering","place":["Xi\u2019an, PR 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Deosaran , NBR1 acts as an autophagy receptor for peroxisomes. J. Cell Sci. 126, 939\u2013952 (2013).","journal-title":"J. Cell Sci."},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-019-1563-3"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.26502\/jbb.2642-91280119"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-0562"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-96-1016-7_8"},{"key":"e_1_3_4_23_2","unstructured":"Q. Su CRISPR screening. OMIX. https:\/\/ngdc.cncb.ac.cn\/omix\/release\/OMIX015678. Deposited 19 March 2026."},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae978"},{"key":"e_1_3_4_25_2","unstructured":"Q. Su Proteomic analysis of D665-1412 treated HCC cells. iProX. https:\/\/www.iprox.cn\/page\/project.html?id=IPX0016315000. Deposited 23 March 2026."},{"key":"e_1_3_4_26_2","unstructured":"Q. Su Fatty acid analysis in HCC samples. iProX. https:\/\/www.iprox.cn\/page\/project.html?id=IPX0016195000. Deposited 18 March 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2535777123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T17:36:46Z","timestamp":1781026606000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2535777123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,9]]},"references-count":26,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2026,6,16]]}},"alternative-id":["10.1073\/pnas.2535777123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2535777123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,9]]},"assertion":[{"value":"2025-12-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2535777123"}}