Wang Junrui, Tian Haoyuan, Gao Yuanyuan, Qiu Xinran, Bao Zhengyang, Zhao Danli, Zhang Feng, Zhang Zili, Wang Feixia, Zheng Shizhong, Cheng Haibo, Shao Jiangjuan
Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing 210023, China.
Research (Wash D C). 2025 Aug 7;8:0808. doi: 10.34133/research.0808. eCollection 2025.
Activation of hepatic stellate cells (HSCs) represents a central pathological event in liver fibrogenesis, and targeted clearance of activated HSCs is considered to be a promising therapeutic strategy. However, our understanding of the underlying molecular mechanisms is limited. Here, we report that Oroxylin A (OA) inhibited the activation of HSCs by inhibiting the dual roles of Sirtuin 7 (SIRT7). Single-cell transcriptome sequencing analysis and bioinformatics analysis were employed to identify critical pathways, followed by validation through molecular assays including Western blotting, immunofluorescence, and co-immunoprecipitation. In human samples, animal models, and primary cultures, the translational relevance of molecular discoveries was heightened. OA binds to the Gln299 and Asp305 residues of SIRT7, triggering a dual regulatory program in hepatic fibrosis. OA suppresses SIRT7, triggering succinylation-dependent proteasomal degradation of protein arginine methyltransferase 5 (PRMT5). This cascade attenuated symmetric dimethylation of cyclic GMP-AMP synthase (cGAS), thereby activating the cGAS-stimulator of interferon genes (STING) signaling and promoting HSC senescence. Concurrently, OA-elicited SIRT7 inhibition promotes externalized calreticulin (ecto-CRT) expression, thereby enhancing natural killer (NK) cell recognition and targeted elimination of activated HSCs. However, enzymatically dead mutant SIRT7 (H187Y) also suppressed ecto-CRT expression promoted by OA, showing that it is independent of its desuccinylase activity. Our findings reveal a dual regulatory mechanism whereby SIRT7 inhibition by OA coordinates PRMT5 degradation-mediated cellular senescence and ecto-CRT-dependent NK cell immune clearance of HSCs. This work establishes SIRT7 as a pivotal therapeutic target and provides mechanistic insights for developing antifibrotic strategies.
肝星状细胞（HSCs）的激活是肝纤维化发生过程中的核心病理事件，靶向清除活化的HSCs被认为是一种有前景的治疗策略。然而，我们对其潜在分子机制的了解有限。在此，我们报告木犀草素A（OA）通过抑制沉默调节蛋白7（SIRT7）的双重作用来抑制HSCs的激活。采用单细胞转录组测序分析和生物信息学分析来确定关键途径，随后通过蛋白质印迹、免疫荧光和免疫共沉淀等分子检测进行验证。在人类样本、动物模型和原代培养中，分子发现的转化相关性得到了增强。OA与SIRT7的Gln299和Asp305残基结合，在肝纤维化中触发双重调节程序。OA抑制SIRT7，引发蛋白质精氨酸甲基转移酶5（PRMT5）的琥珀酰化依赖性蛋白酶体降解。这一级联反应减弱了环磷酸鸟苷-腺苷酸合成酶（cGAS）的对称二甲基化，从而激活cGAS-干扰素基因刺激因子（STING）信号通路并促进HSCs衰老。同时，OA诱导的SIRT7抑制促进了膜联钙网蛋白（ecto-CRT）的表达，从而增强自然杀伤（NK）细胞对活化HSCs的识别和靶向清除。然而，酶失活的突变体SIRT7（H187Y）也抑制了OA促进的ecto-CRT表达，表明这一过程独立于其去琥珀酰化酶活性。我们的研究结果揭示了一种双重调节机制，即OA对SIRT7的抑制作用协调了PRMT5降解介导的细胞衰老和ecto-CRT依赖的NK细胞对HSCs的免疫清除。这项工作将SIRT7确立为关键的治疗靶点，并为开发抗纤维化策略提供了机制性见解。
