Oroxyloside抑制肝纤维化和肝癌发生依赖于肝细胞特异性敲除Atg5

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-07-06 DOI:10.1016/j.phymed.2025.157053

Yunyao Liu , Liu Chen , Xingyu Liu , Ran Tao , Ran Dong , Xiaosheng Wang , Jiangti Luo , Hanhan Li , Yufen Zheng , Lei Qiang , Zhenzhong Deng , Xiaoping Wang

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引用次数: 0

摘要

背景,肝细胞癌（HCC）是癌症相关死亡的主要原因，与肝纤维化密切相关，但有效的预防治疗仍然难以捉摸。自噬是维持肝脏稳态的关键细胞过程，其破坏与纤维化和HCC的进展有关。本研究旨在评价黄芩中提取的黄酮类化合物oroxyloside （OAG）对肝癌肝纤维化的预防作用。方法采用四氯化碳（CCl4）单独或联合二乙基亚硝胺（DEN），在OAG治疗或不治疗的情况下，建立小鼠肝纤维化和肝癌发生模型。采用肝细胞特异性Atg5敲除小鼠（Atg5Hep-/−）和体外模型（沉默Atg5或PPARγ）研究自噬在OAG治疗效果中的作用。为了分析自噬与肝纤维化或癌症的相关性，我们使用TCGA和GSE数据库。患者组织样本（79对）相关HCC进行免疫组化研究。结果OAG通过AMPK-ULK1通路以ppar γ依赖的方式恢复自噬通量，减少氧化应激、DNA损伤和炎症细胞因子IL-6的产生。这些机制最终抑制了肝星状细胞的活化和纤维化的进展。在慢性肝损伤模型中，OAG还能显著减轻肝脏肿瘤负荷，提高生存率。重要的是，OAG的治疗效果在atg5缺陷肝细胞中减弱，突出了其对自噬的依赖。通过靶向自噬和炎症之间的相互作用，这种机制将OAG与现有的抗纤维化或HCC治疗区分开来。结论oag通过自噬依赖途径抑制炎症和氧化应激，是一种治疗肝纤维化和HCC的创新方法。它的双重抗纤维化和抗癌作用使OAG成为解决慢性肝病未满足的临床需求的有希望的候选者。

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

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 (Atg5^Hep-/−) 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.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.