2. Academic Validation
  3. Oroxyloside inhibits liver fibrosis and hepatocarcinogenesis dependent on hepatocyte-specific knockout of Atg5

Oroxyloside inhibits liver fibrosis and hepatocarcinogenesis dependent on hepatocyte-specific knockout of Atg5

  • Phytomedicine. 2025 Sep:145:157053. doi: 10.1016/j.phymed.2025.157053.
Yunyao Liu 1,  Liu Chen 2,  Xingyu Liu 2,  Ran Tao 2,  Ran Dong 2,  Xiaosheng Wang 3,  Jiangti Luo 4,  Hanhan Li 4,  Yufen Zheng 5,  Lei Qiang 6,  Zhenzhong Deng 7,  Xiaoping Wang 8
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing 210042, PR China.
  • 2 State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China.
  • 3 Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, PR China.
  • 4 Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, PR China.
  • 5 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China.
  • 6 State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing 210042, PR China.
  • 7 Department of Oncology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, PR China. Electronic address: dengzhezhong@xinhuanmed.com.cn.
  • 8 State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China. Electronic address: xiaopingwang@cpu.edu.cn.
PMID: 40663935 DOI: 10.1016/j.phymed.2025.157053
Abstract

Background & aims: Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, is closely linked to liver fibrosis, yet effective preventive therapies remain elusive. Autophagy is a critical cellular process that maintains hepatic homeostasis, and its disruption is implicated in the progression of fibrosis and HCC. This study aimed to evaluate the efficacy of oroxyloside (OAG), a flavonoid derived from Scutellaria baicalensis, in preventing liver fibrosis associated with Cancer.

Methods: Mouse models of liver fibrosis and hepatocarcinogenesis were developed using carbon tetrachloride (CCl4) alone or a combined with diethylnitrosamine (DEN), with or without OAG treatment. Hepatocyte-specific Atg5 knockout mice (Atg5Hep-/-) and In vitro models with silenced Atg5 or PPARγ were used to investigate autophagy's role in OAG's therapeutic effects. To analyze the correlation between Autophagy and hepatic fibrosis or Cancer we use the TCGA and GSE database. Patient tissue samples (79 pairs) associated HCC was investigated by immunohistochemistry.

Results: This study demonstrates that OAG restores autophagic flux through the AMPK-ULK1 pathway in a PPARγ-dependent manner, reducing oxidative stress, DNA damage, and inflammatory cytokine IL-6 production. These mechanisms culminate in the inhibiting the activation of hepatic stellate cell activation and fibrosis progression. OAG also significantly attenuated liver tumor burden and improved survival in a chronic liver injury model. Importantly, the therapeutic effects of OAG were diminished in Atg5-deficient hepatocytes, highlighting its reliance on Autophagy. This mechanistic insight differentiates OAG from existing anti-fibrotic or HCC therapies by targeting the interplay between Autophagy and inflammation.

Conclusion: OAG represents an innovative therapeutic approach to liver fibrosis and HCC, acting through autophagy-dependent pathways to inhibit inflammation and oxidative stress. Its dual anti-fibrotic and anti-carcinogenic effects position OAG as a promising candidate for addressing the unmet clinical needs in chronic liver disease.

Keywords

Atg5; Autophagy; IL-6; Liver Fibrosis; Oroxyloside.

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