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The analysis of human hepatic single-nucleus RNA sequencing (snRNA-seq) data revealed predominant up-regulation of\n            <jats:italic toggle=\"yes\">SPTLC2<\/jats:italic>\n            , which encodes a subunit of the rate-limiting enzyme in the de novo ceramide synthesis pathway, in hepatocytes. By targeted inhibition of SPTLC2 with lipid nanoparticle\u2013mediated siRNA delivery to hepatocytes, we reduced both hepatic and circulating ceramide levels. This intervention suppressed hepatic lipid uptake and lipogenesis, thereby alleviating MASH progression. Therapeutic efficacy was demonstrated in an 8-week methionine-choline\u2013deficient diet-induced MASH model and validated in a 1-year choline-deficient high-fat diet\u2013induced MASH model. Our findings highlight hepatocyte\n            <jats:italic toggle=\"yes\">Sptlc2<\/jats:italic>\n            as a promising therapeutic target for MASH.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adx2681","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T17:58:32Z","timestamp":1758909512000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":31,"title":["Targeted inhibition of hepatic de novo ceramide synthesis ameliorates MASH"],"prefix":"10.1126","volume":"11","author":[{"given":"Xiaodong","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore."},{"name":"Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117609, 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