{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T18:47:57Z","timestamp":1782499677369,"version":"3.54.5"},"reference-count":41,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"26","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172241"],"award-info":[{"award-number":["82172241"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82341066"],"award-info":[{"award-number":["82341066"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangdong Hong Kong Macao University Joint Laboratory of Interventional Medicine Foundation of Guangdong Province","award":["2023LSYS001"],"award-info":[{"award-number":["2023LSYS001"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,6,26]]},"abstract":"<jats:p>\n                    Metabolic reprogramming is a hallmark of cancer, yet the critical drivers and mechanisms in hepatocellular carcinoma (HCC) remain incompletely understood. Through a metabolism-focused CRISPR screen, we identified phosphomevalonate kinase (PMVK), a mevalonate pathway enzyme, as a key regulator of HCC stemness and progression. PMVK directly phosphorylates the transcription factor SP1 at Thr\n                    <jats:sup>355<\/jats:sup>\n                    , which enhances SP1\u2019s DNA binding affinity and promotes its interaction with the master lipid regulator SREBP1\/2, driving a transcriptional program essential for de novo cholesterol and fatty acid synthesis. Clinically, PMVK levels are positively correlated with phospho-SP1 (Thr\n                    <jats:sup>355<\/jats:sup>\n                    ) levels and predicate poor prognosis in patients with HCC. Functionally, we demonstrate that genetic or pharmacologic inhibition of the PMVK-SP1 axis, including using the SP1 inhibitor mithramycin A (MTA), significantly suppresses HCC tumorigenesis. In conclusion, our findings uncover the PMVK-SP1 axis as a central driver of lipid metabolic reprogramming and hepatocarcinogenesis, highlighting it as a compelling therapeutic target in HCC.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aed8866","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T17:59:33Z","timestamp":1782496773000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["PMVK drives hepatocarcinogenesis via SP1 phosphorylation\u2013mediated lipid metabolic reprogramming"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8664-7308","authenticated-orcid":true,"given":"Ruiyang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China."},{"name":"Guangdong Provincial Engineering Research Center of Molecular 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