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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.<\/jats:p>","DOI":"10.34133\/research.0808","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T04:40:40Z","timestamp":1752122440000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":6,"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"],"prefix":"10.34133","volume":"8","author":[{"given":"Junrui","family":"Wang","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, \rNanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyuan","family":"Tian","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, \rNanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, \rNanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinran","family":"Qiu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, \rNanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyang","family":"Bao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, \rNanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danli","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, \rNanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zili","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, \rNanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feixia","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, \rNanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizhong","family":"Zheng","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, \rNanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Cheng","sequence":"additional","affiliation":[{"name":"Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7658-9884","authenticated-orcid":true,"given":"Jiangjuan","family":"Shao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, \rNanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-023-00807-x"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.34133\/research.0435"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32075"},{"issue":"1","key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.5152\/tjg.2018.17330","article-title":"Liver fibrosis","volume":"29","author":"Ayd\u0131n MM","year":"2018","unstructured":"Ayd\u0131n MM, Ak\u00e7al\u0131 KC. 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