{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T05:30:36Z","timestamp":1786339836496,"version":"build-2736575974"},"reference-count":56,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070590"],"award-info":[{"award-number":["82070590"]}],"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":["82373930"],"award-info":[{"award-number":["82373930"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Hepatic steatosis, caused by lipid homeostasis disruption, is implicated in the pathogenesis of metabolic dysfunction\u2010associated steatotic liver disease (MASLD). Sphingosine kinase 2 (SPHK2), a pivotal modulator of sphingolipid catabolism, participates in hepatic lipid accumulation. Non\u2010enzymatic regulation of SPHK2 is gaining more attention. We aimed to elucidate the non\u2010canonical mechanism by which SPHK2 mediates hepatic steatosis independent of its enzymatic activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      By analysing single\u2010cell transcriptome profile of mouse hepatocytes with MASLD confirms that SPHK2 is involved in the progression of hepatic steatosis. Gain or loss of function of SPHK2 was performed using mice with hepatocyte\u2010specific overexpression or knockout\n                      <jats:italic>Sphk2<\/jats:italic>\n                      . Integrated multi\u2010omics approach and immunoprecipitation\u2010mass spectrometry were employed to elucidate the role and molecular mechanism of SPHK2 in steatotic livers. Adeno\u2010associated virus 8 (AAV8) vectors were used to overexpress a catalytically inactive form of SPHK2 in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Hepatocyte SPHK2 was significantly downregulated in steatotic livers from patients and mice with MASLD. Hepatocyte knockout of\n                      <jats:italic>Sphk2<\/jats:italic>\n                      promotes diet\u2010induced hepatic steatosis by inhibiting adipose triglyceride lipase\/patatin like domain 2, triacylglycerol lipase (ATGL)\u2010mediated triglyceride hydrolysis, whereas hepatocyte overexpression of SPHK2 attenuated high\u2010fat diet (HFD)\u2010induced hepatic steatosis by stabilizing ATGL. SPHK2 bound to ATGL, inhibiting COP1\u2010mediated ATGL ubiquitination. Furthermore, kruppel\u2010like factor 10 (KLF10) was identified as a transcription repressor responsible for downregulation of SPHK2 in hepatocytes. Over overexpression of the non\u2010catalytic function of SPHK2 prevented hepatic steatosis in diet\u2010induced mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>SPHK2 attenuates hepatic steatosis by enzymatic\u2010independently inhibiting ATGL ubiquitination and promoting triglyceride hydrolysis, indicating its therapeutic potential for MASLD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70397","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T08:03:57Z","timestamp":1773129837000},"page":"3272-3292","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Noncanonical function of sphingosine kinase 2 (SPHK2) sustains hepatic triglyceride 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