{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:56:59Z","timestamp":1785430619626,"version":"3.56.0"},"reference-count":27,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:00:00Z","timestamp":1782604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CACMS Innovation Fund","award":["CI2026A01519"],"award-info":[{"award-number":["CI2026A01519"]}]},{"name":"CACMS Innovation Fund","award":["CI2026A01502"],"award-info":[{"award-number":["CI2026A01502"]}]},{"name":"CACMS Innovation Fund","award":["CI2026A01501"],"award-info":[{"award-number":["CI2026A01501"]}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2025YFC3512804"],"award-info":[{"award-number":["2025YFC3512804"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82575037"],"award-info":[{"award-number":["82575037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82575037"],"award-info":[{"award-number":["82575037"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Fundamental Research Funds for the Central Public Welfare Research Institutes","award":["YZX-202317"],"award-info":[{"award-number":["YZX-202317"]}]},{"name":"Key R&D and Transformation Plan Project of Qinghai Province","award":["2025-QY-212"],"award-info":[{"award-number":["2025-QY-212"]}]},{"name":"2023 Kunlun High-end Innovation and Entrepreneurship Talents Project of Qinghai Province\u2014Training of leading talents","award":["QHKLYC-GDCXCY-2023-313"],"award-info":[{"award-number":["QHKLYC-GDCXCY-2023-313"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background: Autoimmune diseases such as primary Sj\u00f6gren\u2019s syndrome and type 1 diabetes are frequently complicated by hepatic injury, yet therapies that simultaneously target inflammation and parenchymal damage remain limited. Mitochondrial dysfunction with excessive reactive oxygen species (ROS) production drives a self-amplifying pathogenic loop by activating the cGAS-STING innate immune pathway. We previously observed that a Chinese herbal formula preserved mitochondrial ultrastructure in autoimmune NOD mice, and computational screening identified trifolirhizin\u2014a natural pterocarpan flavonoid\u2014as the candidate active constituent mediating this protection. Here, we investigated the hepatoprotective effects and underlying mechanisms of trifolirhizin in autoimmune-associated liver injury. Methods: Female NOD mice received trifolirhizin (5, 10, or 20 mg\/kg\/day) for four weeks, with C57BL\/6J mice as healthy controls. Hepatic histopathology, inflammatory cytokines, mitochondrial ultrastructure (TEM), mitochondrial membrane potential (\u0394\u03a8m), and ROS levels were evaluated. Integrated transcriptomic and metabolomic profiling was performed to unbiasedly characterize protective mechanisms. In vitro, H2O2-induced oxidative stress was established in HepG2 cells. Cells were treated with trifolirhizin (15\u201325 \u00b5M) and assessed for antioxidant enzyme activities, \u0394\u03a8m, ROS production, glycolytic and mitochondrial respiration (Seahorse analysis), and cGAS-STING pathway protein expression. Pharmacological rescue experiments using the cGAS agonist cGAMP were conducted to test pathway dependency. Results: Trifolirhizin dose-dependently alleviated hepatic pathological damage and reduced pro-inflammatory cytokine levels in NOD mice. Multi-omics profiling revealed that oxidative stress responses, the mitochondrial electron transport chain, and glutathione metabolism were the most significantly restored pathways. Trifolirhizin preserved mitochondrial ultrastructure, restored \u0394\u03a8m, and attenuated ROS accumulation both in vivo and in vitro. Functionally, Seahorse analysis demonstrated that trifolirhizin rescued overall cellular bioenergetics, restoring both glycolytic capacity and mitochondrial respiratory parameters (basal respiration, ATP production, maximal respiration, and spare respiratory capacity). Mechanistically, trifolirhizin suppressed the cGAS-STING-TBK1-IRF3 axis, as evidenced by reduced expression of cGAS, p-STING, ZBP1, p-TBK1, and p-IRF3. Importantly, the cGAS agonist cGAMP abrogated the protective effects of trifolirhizin, confirming that the cGAS-STING pathway is functionally required for its action downstream of mitochondrial protection. Conclusion: Trifolirhizin attenuates liver injury in the nod mouse by preserving mitochondrial integrity, maintaining cellular energy metabolism, and thereby suppressing the ROS\/cGAS-STING inflammatory cascade. These findings position trifolirhizin as a promising mitochondria-targeted therapeutic candidate for pSS-related hepatic complications and provide a mechanistic framework for discovering active compounds from mitochondrially active herbal formulations.<\/jats:p>","DOI":"10.3390\/antiox15070814","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T10:01:17Z","timestamp":1782813677000},"page":"814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial Protection by Trifolirhizin Alleviates Primary Sj\u00f6gren\u2019s Syndrome and Liver Injury via Coordinated Suppression of the ROS\/cGAS-STING Pathway"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9755-1772","authenticated-orcid":false,"given":"Haotian","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"},{"name":"Department of Digestive Disorders, Beijing Key Laboratory of Diagnosis and Treatment of Functional Gastrointestinal Diseases of Traditional Chinese Medicine, Beijing 100102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Han","sequence":"additional","affiliation":[{"name":"Capital Institute of Rheumatology and Immunology of Integrated Medicine, Beijing 100032, China"},{"name":"Precision Al in Rheumatology Network, Beijing 100032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rouman","family":"Zhang","sequence":"additional","affiliation":[{"name":"Capital Institute of Rheumatology and Immunology of Integrated Medicine, Beijing 100032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congmin","family":"Xia","sequence":"additional","affiliation":[{"name":"Capital Institute of Rheumatology and Immunology of Integrated Medicine, Beijing 100032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Digestive Disorders, Beijing Key Laboratory of Diagnosis and Treatment of Functional Gastrointestinal Diseases of Traditional Chinese Medicine, Beijing 100102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8514-5871","authenticated-orcid":false,"given":"Yanjun","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"},{"name":"Precision Al in Rheumatology Network, Beijing 100032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2935-4311","authenticated-orcid":false,"given":"Yuping","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Capital Institute of Rheumatology and Immunology of Integrated Medicine, Beijing 100032, China"},{"name":"Precision Al in Rheumatology Network, Beijing 100032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.3748\/wjg.v28.i23.2527","article-title":"Autoimmune liver diseases in systemic rheumatic diseases","volume":"28","author":"Wang","year":"2022","journal-title":"World J. 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