Scholarlink

<p>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-NASH (GAN)-diet-induced MASH models. In TGF-β1-activated human HSCs cell line (LX-2 cells), 8-HETrE treatment suppressed fibrotic markers (α-SMA, COL1A1) and improved mitochondrial dynamics. Mechanistic investigations revealed that 8-HETrE exerted its anti-fibrotic effects primarily through SPHK1 inhibition: SPHK1 knockdown moderately reduced HSC activation, decreased sphingosine-1-phosphate (S1P), lactate, and nitrite levels, enhanced glucose uptake, and promoted mitochondrial fusion, while completely abolishing 8-HETrE's therapeutic effects. Conversely, SPHK1 overexpression exacerbated fibrotic and metabolic abnormalities, which were effectively reversed by 8-HETrE treatment. Critically, HSC-specific Sphk1 knockout independently improved MASH fibrosis, mitochondrial function, and metabolic parameters, while completely blocking 8-HETrE's benefits. Our findings identify 8-HETrE as a novel mediator that targets the SPHK1-mitochondrial dynamics axis in HSCs, providing both mechanistic insights and therapeutic potential for MASH-related fibrosis treatment.</p> Graphical abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月17日

查看全文
  • Shuling Chen,
  • Jiayan Li,
  • Kan Xu,
  • Junyi Wen,
  • Feng Zhang,
  • Yuzheng Zhuge,
  • Lei Wang,
  • Yongxiang Yi,
  • Hao Zhang,
  • Wei Zhang

摘要

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-NASH (GAN)-diet-induced MASH models. In TGF-β1-activated human HSCs cell line (LX-2 cells), 8-HETrE treatment suppressed fibrotic markers (α-SMA, COL1A1) and improved mitochondrial dynamics. Mechanistic investigations revealed that 8-HETrE exerted its anti-fibrotic effects primarily through SPHK1 inhibition: SPHK1 knockdown moderately reduced HSC activation, decreased sphingosine-1-phosphate (S1P), lactate, and nitrite levels, enhanced glucose uptake, and promoted mitochondrial fusion, while completely abolishing 8-HETrE's therapeutic effects. Conversely, SPHK1 overexpression exacerbated fibrotic and metabolic abnormalities, which were effectively reversed by 8-HETrE treatment. Critically, HSC-specific Sphk1 knockout independently improved MASH fibrosis, mitochondrial function, and metabolic parameters, while completely blocking 8-HETrE's benefits. Our findings identify 8-HETrE as a novel mediator that targets the SPHK1-mitochondrial dynamics axis in HSCs, providing both mechanistic insights and therapeutic potential for MASH-related fibrosis treatment.

Graphical abstract