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However, high levels of dietary cholesterol still promote excessive cholesterol accumulation in the liver, leading to metabolic dysfunction\u2013associated steatohepatitis (MASH), yet the mechanisms remain poorly understood. Here, we show that hepatic S100 calcium-binding protein A11 (S100A11), a member of the S100 family of calcium-binding proteins, positively responded to dietary cholesterol levels and was involved in hepatic cholesterol metabolism. S100A11 localized to the ER and could bind to cholesterol. In vivo and in vitro, hepatic overexpression of S100A11 led to sterol regulatory element\u2013binding transcription factor 2 (SREBP2) activation to promote cholesterol synthesis, uptake, and accumulation, consequently exacerbating steatohepatitis. In contrast, inactivation of S100A11 had opposite effects and improved steatohepatitis. Mechanistically, S100A11 triggered the noncanonical entry of SREBP2 into the nucleus through a S100A11\/annexin A1\/importin \u03b2 (S100A11\/ANXA1\/KPNB) axis, distinct from the well-known insulin-induced gene \/SREBP cleavage-activating protein or caspase 2 pathways. Therefore, our work identifies S100A11 as a regulator of liver cholesterol metabolism, providing a promising target to treat MASH and hypercholesterolemia.<\/jats:p>","DOI":"10.1172\/jci201406","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T16:00:31Z","timestamp":1785859231000},"source":"Crossref","is-referenced-by-count":0,"title":["S100A11 regulates hepatic cholesterol metabolism and promotes steatohepatitis via noncanonical SREBP2 signaling"],"prefix":"10.1172","volume":"136","author":[{"given":"Mingfeng","family":"Zhan","sequence":"first","affiliation":[{"name":"School of Life Sciences, Yunnan Key Laboratory of Cell Metabolism and Diseases, Yunnan University, Kunming, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumei","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, 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