Targeting SPHK1 by 8-HETrE attenuates MASH-Driven fibrosis via restoration of hepatic stellate cell mitochondrial dynamics.

ABSTRACT: Metabolic dysfunction-associated steatohepatitis (MASH) drives hepatic stellate cell (HSC) activation and extracellular matrix deposition, leading to liver fibrosis, for which effective treatments remain lacking. Here, we report that 8-hydroxyoctacosatrienoic acid (8-HETrE), an arachidonic acid metabolite generated through cytochrome P450 or lipoxygenase pathways, significantly ameliorates MASH-related fibrosis by targeting sphingosine kinase 1 (SPHK1) and restoring mitochondrial function. Clinical observations revealed markedly reduced circulating 8-HETrE levels in patients with MASH fibrosis. In vivo studies demonstrated that 8-HETrE administration improved liver function, enhanced expression of mitochondrial fusion proteins (Mfn1, Mfn2, Opa1), and attenuated fibrosis in Gubra-Amylin-NAS

SUBMITTER: Chen S 

PROVIDER: S-EPMC12835092 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature