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A nonobese NAFLD rat model was established using a high\u2010temperature dry\u2010fried soybean diet. Integrated liquid chromatography\u2010mass spectrometry\u2010based proteomic and metabolomic analyses were used to identify candidate pathways. Sptlc2 function was validated by AAV2\/8\u2010mediated liver\u2010directed knockdown in vivo, lentiviral knockdown in primary hepatocytes, and C2\u2010ceramide rescue experiments. Multi\u2010omics profiling identified Sptlc2 as a sphingolipid metabolism\u2010related candidate in the model. Sptlc2 knockdown reduced long\u2010chain ceramide accumulation, hepatic lipid deposition, inflammatory cytokine expression, oxidative stress, and hepatocyte injury. In primary hepatocytes, Sptlc2 silencing improved mitochondrial respiration, membrane potential, calcium and reactive oxygen species homeostasis, and\u00a0mitochondrial ultrastructure. These protective effects were partially reversed by C2\u2010ceramide in vitro and in vivo. The Sptlc2\u2013ceramide axis contributes to ceramide accumulation, hepatic lipotoxicity, inflammatory activation, and mitochondrial dysfunction in this nonobese NAFLD model, suggesting its potential relevance as a therapeutic target for further investigation.<\/jats:p>","DOI":"10.1002\/ccs3.70091","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T12:17:53Z","timestamp":1782389873000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ceramide\u2010mediated mitochondrial dysfunction in nonobese nonalcoholic fatty liver disease: A regulatory role for serine palmitoyltransferase subunit 2"],"prefix":"10.1002","volume":"20","author":[{"given":"Li\u2010Jun","family":"Xue","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Jinan Central Hospital Affiliated to Shandong First Medical University  Jinan Shandong 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