Scutellarin Alleviates Hepatic Steatosis by Autophagy‐Mediated NCoR1 / PPARα ‐Driven Fatty Acid β‐Oxidation and Enhancing Peroxisome Biogenesis
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2026
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| author | Jianmei Zheng Lu Cheng Yingmin Wei Mingshi Ren Lei Wang Jingwen Wang Wuliu Zhou Hui Huang Feihua Wu |
| author_facet | Jianmei Zheng Lu Cheng Yingmin Wei Mingshi Ren Lei Wang Jingwen Wang Wuliu Zhou Hui Huang Feihua Wu Jianmei Zheng Lu Cheng Yingmin Wei Mingshi Ren Lei Wang Jingwen Wang Wuliu Zhou Hui Huang Feihua Wu |
| collection | Wiley Open Access |
| contents | Scutellarin Alleviates Hepatic Steatosis by Autophagy‐Mediated NCoR1 / PPARα ‐Driven Fatty Acid β‐Oxidation and Enhancing Peroxisome Biogenesis Jianmei Zheng Lu Cheng Yingmin Wei Mingshi Ren Lei Wang Jingwen Wang Wuliu Zhou Hui Huang Feihua Wu Phytotherapy Research ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder with limited treatment and manifests as hepatic lipid accumulation. The reduction of nuclear receptor corepressor 1 (NCoR1) activates the nuclear receptor PPARα, which plays a crucial role in alleviating lipid accumulation. We found that Scutellarin (Scu) regulated autophagy‐mediated NCoR1/PPARα to enhance fatty acid (FA) β‐oxidation and peroxisome production, thereby alleviating the lipid accumulation of MASLD. We used palmitic acid (PA)‐treated human hepatocellular carcinoma (HepG2) and alpha mouse liver 12 (AML12) cells, as well as high‐fat diet‐fed C57BL/6J mice to evaluate the protective effect of Scu on MASLD. Scu reduced the levels of total cholesterol, triglycerides, and lipid droplets, whereas it dose‐dependently increased the levels of β‐hydroxybutyrate. In addition, Scu increased mRNA and protein expression of PPARα and promoted the transcriptional activity of FA β‐oxidation‐related target genes. In vitro, inhibition of PPARα with small interfering RNA (siRNA) abolished the activation of FA β‐oxidation by Scu. Cellular thermal shift assay and drug affinity responsive target stability demonstrated that Scu did not interact directly with PPARα. Moreover, Scu increased the protein expression of 70‐kDa peroxisomal membrane protein and the mRNA expression of peroxisome biogenesis‐related genes. These effects were reversed by PPARα‐siRNA. Scu improved the impaired autophagy while reducing the mRNA and protein expression of NCoR1. Notably, Scu reduced the colocalization of NCoR1 with PPARα and increased its colocalization with the autophagosome GABARAP. 3‐MA, an autophagy inhibitor, attenuated Scu‐mediated protective effects by FA β‐oxidation and peroxisome biogenesis both in vitro and in vivo. In summary, Scu reduces lipid accumulation by improving the impaired autophagy, decreasing NCoR1 expression to activate PPARα, thereby simultaneously enhancing FA β‐oxidation and peroxisome biogenesis, ultimately ameliorating hepatic steatosis. 10.1002/ptr.70367 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1002/ptr.70367 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_ptr_70367 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2026 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Scutellarin Alleviates Hepatic Steatosis by Autophagy‐Mediated NCoR1 / PPARα ‐Driven Fatty Acid β‐Oxidation and Enhancing Peroxisome Biogenesis Jianmei Zheng Lu Cheng Yingmin Wei Mingshi Ren Lei Wang Jingwen Wang Wuliu Zhou Hui Huang Feihua Wu Phytotherapy Research Scutellarin Alleviates Hepatic Steatosis by Autophagy‐Mediated NCoR1 / PPARα ‐Driven Fatty Acid β‐Oxidation and Enhancing Peroxisome Biogenesis Jianmei Zheng Lu Cheng Yingmin Wei Mingshi Ren Lei Wang Jingwen Wang Wuliu Zhou Hui Huang Feihua Wu Phytotherapy Research ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder with limited treatment and manifests as hepatic lipid accumulation. The reduction of nuclear receptor corepressor 1 (NCoR1) activates the nuclear receptor PPARα, which plays a crucial role in alleviating lipid accumulation. We found that Scutellarin (Scu) regulated autophagy‐mediated NCoR1/PPARα to enhance fatty acid (FA) β‐oxidation and peroxisome production, thereby alleviating the lipid accumulation of MASLD. We used palmitic acid (PA)‐treated human hepatocellular carcinoma (HepG2) and alpha mouse liver 12 (AML12) cells, as well as high‐fat diet‐fed C57BL/6J mice to evaluate the protective effect of Scu on MASLD. Scu reduced the levels of total cholesterol, triglycerides, and lipid droplets, whereas it dose‐dependently increased the levels of β‐hydroxybutyrate. In addition, Scu increased mRNA and protein expression of PPARα and promoted the transcriptional activity of FA β‐oxidation‐related target genes. In vitro, inhibition of PPARα with small interfering RNA (siRNA) abolished the activation of FA β‐oxidation by Scu. Cellular thermal shift assay and drug affinity responsive target stability demonstrated that Scu did not interact directly with PPARα. Moreover, Scu increased the protein expression of 70‐kDa peroxisomal membrane protein and the mRNA expression of peroxisome biogenesis‐related genes. These effects were reversed by PPARα‐siRNA. Scu improved the impaired autophagy while reducing the mRNA and protein expression of NCoR1. Notably, Scu reduced the colocalization of NCoR1 with PPARα and increased its colocalization with the autophagosome GABARAP. 3‐MA, an autophagy inhibitor, attenuated Scu‐mediated protective effects by FA β‐oxidation and peroxisome biogenesis both in vitro and in vivo. In summary, Scu reduces lipid accumulation by improving the impaired autophagy, decreasing NCoR1 expression to activate PPARα, thereby simultaneously enhancing FA β‐oxidation and peroxisome biogenesis, ultimately ameliorating hepatic steatosis. 10.1002/ptr.70367 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | Scutellarin Alleviates Hepatic Steatosis by Autophagy‐Mediated NCoR1 / PPARα ‐Driven Fatty Acid β‐Oxidation and Enhancing Peroxisome Biogenesis |
| topic | Phytotherapy Research |
| url | https://onlinelibrary.wiley.com/doi/10.1002/ptr.70367 |