Dual Roles of SIRT7 Inhibition by Oroxylin A Reprogram HSCs Fate: PRMT5 Succinylation-Driven Senescence and Ecto-Calreticulin-Dependent NK Cell Immune Clearance in Liver Fibrosis
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...
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American Association for the Advancement of Science (AAAS)
2025-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0808 |
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| author | Junrui Wang Haoyuan Tian Yuanyuan Gao Xinran Qiu Zhengyang Bao Danli Zhao Feng Zhang Zili Zhang Feixia Wang Shizhong Zheng Haibo Cheng Jiangjuan Shao |
| author_facet | Junrui Wang Haoyuan Tian Yuanyuan Gao Xinran Qiu Zhengyang Bao Danli Zhao Feng Zhang Zili Zhang Feixia Wang Shizhong Zheng Haibo Cheng Jiangjuan Shao |
| author_sort | Junrui Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2aa06ee8e8b84a99ba6da61fe4575e4c |
| institution | Kabale University |
| issn | 2639-5274 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Research |
| spelling | doaj-art-2aa06ee8e8b84a99ba6da61fe4575e4c2025-08-20T03:45:11ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742025-01-01810.34133/research.0808Dual Roles of SIRT7 Inhibition by Oroxylin A Reprogram HSCs Fate: PRMT5 Succinylation-Driven Senescence and Ecto-Calreticulin-Dependent NK Cell Immune Clearance in Liver FibrosisJunrui Wang0Haoyuan Tian1Yuanyuan Gao2Xinran Qiu3Zhengyang Bao4Danli Zhao5Feng Zhang6Zili Zhang7Feixia Wang8Shizhong Zheng9Haibo Cheng10Jiangjuan Shao11Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, Nanjing University of Chinese Medicine, Nanjing 210023, China.Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, Nanjing University of Chinese Medicine, Nanjing 210023, China.Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, Nanjing University of Chinese Medicine, Nanjing 210023, China.Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, Nanjing University of Chinese Medicine, Nanjing 210023, China.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.Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, Nanjing University of Chinese Medicine, Nanjing 210023, China.Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, Nanjing University of Chinese Medicine, Nanjing 210023, China.Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, Nanjing University of Chinese Medicine, Nanjing 210023, China.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.Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, Nanjing University of Chinese Medicine, Nanjing 210023, China.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.https://spj.science.org/doi/10.34133/research.0808 |
| spellingShingle | Junrui Wang Haoyuan Tian Yuanyuan Gao Xinran Qiu Zhengyang Bao Danli Zhao Feng Zhang Zili Zhang Feixia Wang Shizhong Zheng Haibo Cheng Jiangjuan Shao Dual Roles of SIRT7 Inhibition by Oroxylin A Reprogram HSCs Fate: PRMT5 Succinylation-Driven Senescence and Ecto-Calreticulin-Dependent NK Cell Immune Clearance in Liver Fibrosis Research |
| title | Dual Roles of SIRT7 Inhibition by Oroxylin A Reprogram HSCs Fate: PRMT5 Succinylation-Driven Senescence and Ecto-Calreticulin-Dependent NK Cell Immune Clearance in Liver Fibrosis |
| title_full | Dual Roles of SIRT7 Inhibition by Oroxylin A Reprogram HSCs Fate: PRMT5 Succinylation-Driven Senescence and Ecto-Calreticulin-Dependent NK Cell Immune Clearance in Liver Fibrosis |
| title_fullStr | Dual Roles of SIRT7 Inhibition by Oroxylin A Reprogram HSCs Fate: PRMT5 Succinylation-Driven Senescence and Ecto-Calreticulin-Dependent NK Cell Immune Clearance in Liver Fibrosis |
| title_full_unstemmed | Dual Roles of SIRT7 Inhibition by Oroxylin A Reprogram HSCs Fate: PRMT5 Succinylation-Driven Senescence and Ecto-Calreticulin-Dependent NK Cell Immune Clearance in Liver Fibrosis |
| title_short | Dual Roles of SIRT7 Inhibition by Oroxylin A Reprogram HSCs Fate: PRMT5 Succinylation-Driven Senescence and Ecto-Calreticulin-Dependent NK Cell Immune Clearance in Liver Fibrosis |
| title_sort | dual roles of sirt7 inhibition by oroxylin a reprogram hscs fate prmt5 succinylation driven senescence and ecto calreticulin dependent nk cell immune clearance in liver fibrosis |
| url | https://spj.science.org/doi/10.34133/research.0808 |
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