{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:26:37Z","timestamp":1787199997526,"version":"build-2736575974"},"reference-count":46,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Technology Plan Projects of Xizang Autonomous Region","award":["XZ202601ZY0159"],"award-info":[{"award-number":["XZ202601ZY0159"]}]},{"name":"Lhasa Key Science and Technology Program","award":["LSKJ202542"],"award-info":[{"award-number":["LSKJ202542"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82074578"],"award-info":[{"award-number":["82074578"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82074578"],"award-info":[{"award-number":["82074578"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Objective: Siweixizangmaoru decoction (SXD), a classical Tibetan prescription documented in the medical text Four Medical Tantras, has shown therapeutic activity in experimental rheumatoid arthritis (RA). However, its candidate active constituents and underlying mechanisms remain unclear. Methods: In this study, serum-absorbed constituents following SXD administration were profiled using ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS), and network pharmacology was employed to identify core targets and candidate active constituents of SXD against RA. Candidate active constituents were further screened using cell-based assays, and the selected constituents were quantified using HPLC fingerprint analysis. Both in vivo (CIA rat model) and in vitro (RAW264.7 pyroptosis model) systems were used to investigate the pharmacological effects and mechanisms of SXD. Results: A total of 11 absorbed constituents were identified in the serum of SXD-treated rats, and four preliminary candidate active constituents, including chebulagic acid, kaempferol, gentiopicroside, and berberine, were screened. The combined in vivo and in vitro results showed that SXD attenuated RA progression and reduced inflammatory cytokine levels in rat serum and cell culture supernatants. At the molecular level, SXD increased Pol \u03b2 expression and reduced DNA damage markers, cytosolic dsDNA accumulation, and cGAS\/STING-, NF-\u03baB-, and NLRP3-associated signaling. Pol \u03b2 knockdown partially reduced the effects of SXD. Conclusions: These findings support the partial involvement of Pol \u03b2-associated processes in the anti-arthritic effects of SXD.<\/jats:p>","DOI":"10.3390\/ph19081302","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:06:41Z","timestamp":1787044001000},"page":"1302","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Siweixizangmaoru Decoction Alleviates Rheumatoid Arthritis by Enhancing Pol \u03b2-Mediated Attenuation of DNA Damage and Suppression of cGAS\/STING\/NF-\u03baB\/NLRP3-Associated Pyroptosis"],"prefix":"10.3390","volume":"19","author":[{"given":"Xiaotong","family":"Chu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Engineering and Pharmaceutical Chemistry, School of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering and Pharmaceutical Chemistry, School of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxiang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering and Pharmaceutical Chemistry, School of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfei","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering and Pharmaceutical Chemistry, School of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Medicine, Xizang University, Lhasa 850000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Medicine, Xizang University, Lhasa 850000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyue","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Medicine, Xizang University, Lhasa 850000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifeng","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Nursing, Qingdao Binhai University, Qingdao 266555, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoma","family":"Dongzhi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Medicine, Xizang University, Lhasa 850000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5345-8398","authenticated-orcid":false,"given":"Shan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering and Pharmaceutical Chemistry, School of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6079-1076","authenticated-orcid":false,"given":"Bin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering and Pharmaceutical Chemistry, School of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China"},{"name":"Department of Pharmacy, College of Medicine, Xizang University, Lhasa 850000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102030","DOI":"10.1016\/j.berh.2024.102030","article-title":"Preclinical RA: How to Halt Its Progression","volume":"39","author":"Wu","year":"2025","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/s41584-022-00793-5","article-title":"Mechanisms of Joint Destruction in Rheumatoid Arthritis\u2014Immune Cell\u2013Fibroblast\u2013Bone Interactions","volume":"18","author":"Komatsu","year":"2022","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/00045632241285843","article-title":"Biomarkers in the Diagnosis, Prognosis and Management of Rheumatoid Arthritis: A Comprehensive Review","volume":"62","author":"Sahin","year":"2025","journal-title":"Ann. Clin. Biochem. Int. J. Lab. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Wu, D., Li, Y., and Xu, R. (2023). Can Pyroptosis Be a New Target in Rheumatoid Arthritis Treatment?. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1155606"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Dai, Z., Liu, W.-C., Chen, X.-Y., Wang, X., Li, J.-L., and Zhang, X. (2023). Gasdermin D-Mediated Pyroptosis: Mechanisms, Diseases, and Inhibitors. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1178662"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2448","DOI":"10.1111\/jcmm.17834","article-title":"Pyroptosis by NLRP3\/Caspase-1\/GASDERMIN-D Pathway in Synovial Tissues of Rheumatoid Arthritis Patients","volume":"27","author":"Zhang","year":"2023","journal-title":"J. Cell. Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41419-022-05047-6","article-title":"A Novel Mechanism for Macrophage Pyroptosis in Rheumatoid Arthritis Induced by Pol \u03b2 Deficiency","volume":"13","author":"Gu","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Galita, G., Brzezi\u0144ska, O., Gulbas, I., Sarnik, J., Poplawska, M., Makowska, J., and Poplawski, T. (2020). Increased Sensitivity of PBMCs Isolated from Patients with Rheumatoid Arthritis to DNA Damaging Agents Is Connected with Inefficient DNA Repair. J. Clin. Med., 9.","DOI":"10.3390\/jcm9040988"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e005774","DOI":"10.1136\/rmdopen-2025-005774","article-title":"RA-Risk Synovium Exhibits DNA Damage Coupled with Impaired DNA Repair in Fibroblasts","volume":"12","author":"Semmelink","year":"2026","journal-title":"RMD Open"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/nrrheum.2010.179","article-title":"Current View of Glucocorticoid Co-Therapy with DMARDs in Rheumatoid Arthritis","volume":"6","author":"Hoes","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.biopha.2018.07.027","article-title":"Novel Drug Delivery Systems for NSAIDs in Management of Rheumatoid Arthritis: An Overview","volume":"106","author":"Thakur","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1186\/s13018-020-01883-4","article-title":"The Prevalence of Rheumatoid Arthritis in Middle-Aged and Elderly People Living in Naqu City, Tibet, Autonomous Region of China","volume":"15","author":"Zhang","year":"2020","journal-title":"J. Orthop. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"119754","DOI":"10.1016\/j.jep.2025.119754","article-title":"Tibetan Medicine Wuwei Leze Powder Improves Inflammatory Mediated Metabolic Disorders and Bone Damage in Collagen-Induced Arthritis Rats","volume":"347","author":"Liu","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"157481","DOI":"10.1016\/j.phymed.2025.157481","article-title":"Qi-Sai-Er-Sang-Dang-Song Decoction Inhibits Pyroptosis and Inflammation in THP-1 Cells and Alleviates Rheumatoid Arthritis by Inhibiting the NLRP3-Pyroptosis Signaling Pathway","volume":"148","author":"Liu","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"116934","DOI":"10.1016\/j.jep.2023.116934","article-title":"Water Extracts of Tibetan Medicine Wuweiganlu Attenuates Experimental Arthritis via Inducing Macrophage Polarization towards the M2 Type","volume":"318","author":"Wen","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_16","unstructured":"Yuthok, Y. (2010). The Four Medical Tantras (rGyud-bZhi), Motilal Banarsidass Publishers."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jep.2004.06.025","article-title":"Inhibitory Effects of the Gentiana Macrophylla (Gentianaceae) Extract on Rheumatoid Arthritis of Rats","volume":"95","author":"Yu","year":"2004","journal-title":"J. Ethnopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1111\/j.2042-7158.2010.01193.x","article-title":"Anti-Arthritic and Disease Modifying Activity of Terminalia Chebula Retz. in Experimental Models","volume":"62","author":"Nair","year":"2010","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Liu, F., Liu, Y., Zhou, D., Dai, Q., and Liu, S. (2015). Anti-Arthritic Effect of Chebulanin on Collagen-Induced Arthritis in Mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0139052"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1248\/bpb.b24-00362","article-title":"Siweixizangmaoru Decoction Ameliorated Type II Collagen-Induced Arthritis in Rats via Regulating JAK2\u2013STAT3 and NF-\u03baB Signaling Pathway","volume":"47","author":"Niu","year":"2024","journal-title":"Biol. Pharm. Bull."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"157249","DOI":"10.1016\/j.phymed.2025.157249","article-title":"Siweixizangmaoru Decoction Attenuates Collagen-Induced Arthritis via Gut Microbiota-Dependent SCFA Restoration and Immunomodulation","volume":"148","author":"Sun","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1093\/jpp\/rgad011","article-title":"The Combination of Astragaloside IV and Panax Notoginseng Saponins Attenuates Cerebral Ischaemia\u2013Reperfusion Injury in Rats through Ferroptosis and Inflammation Inhibition via Activating Nrf2","volume":"75","author":"Kang","year":"2023","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Wu, J.-S., Shi, R., Lu, X., Ma, Y.-M., and Cheng, N.-N. (2015). Combination of Active Components of Xiexin Decoction Ameliorates Renal Fibrosis Through the Inhibition of NF-\u03baB and TGF-\u03921\/Smad Pathways in Db\/Db Diabetic Mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122661"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nrmicro2070","article-title":"Pyroptosis: Host Cell Death and Inflammation","volume":"7","author":"Bergsbaken","year":"2009","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.immuni.2020.05.013","article-title":"Structures and Mechanisms in the cGAS-STING Innate Immunity Pathway","volume":"53","author":"Zhang","year":"2020","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"103050","DOI":"10.1016\/j.dnarep.2021.103050","article-title":"DNA Polymerase \u03b2 Outperforms DNA Polymerase \u03b3 in Key Mitochondrial Base Excision Repair Activities","volume":"99","author":"Baptiste","year":"2021","journal-title":"DNA Repair"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"18001","DOI":"10.1038\/nrdp.2018.1","article-title":"Rheumatoid Arthritis","volume":"4","author":"Smolen","year":"2018","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.clinbiochem.2006.10.006","article-title":"Increased DNA Damage and Oxidative Stress in Patients with Rheumatoid Arthritis","volume":"40","author":"Altindag","year":"2007","journal-title":"Clin. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Liu, Y., and Pu, F. (2023). Updated Roles of cGAS-STING Signaling in Autoimmune Diseases. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1254915"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.clim.2019.03.009","article-title":"DNA Damage Accumulation, Defective Chromatin Organization and Deficient DNA Repair Capacity in Patients with Rheumatoid Arthritis","volume":"203","author":"Souliotis","year":"2019","journal-title":"Clin. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gohil, D., Sarker, A.H., and Roy, R. (2023). Base Excision Repair: Mechanisms and Impact in Biology, Disease, and Medicine. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241814186"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1084\/jem.20180139","article-title":"The cGAS\u2013cGAMP\u2013STING Pathway Connects DNA Damage to Inflammation, Senescence, and Cancer","volume":"215","author":"Li","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.1073\/pnas.1222694110","article-title":"DNA Damage Sensor MRE11 Recognizes Cytosolic Double-Stranded DNA and Induces Type I Interferon by Regulating STING Trafficking","volume":"110","author":"Kondo","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/s41392-021-00554-y","article-title":"Cytosolic DNA Sensing by cGAS: Regulation, Function, and Human Diseases","volume":"6","author":"Yu","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Akbari, M., Shanley, D.P., Bohr, V.A., and Rasmussen, L.J. (2021). Cytosolic Self-DNA\u2014A Potential Source of Chronic Inflammation in Aging. Cells, 10.","DOI":"10.3390\/cells10123544"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1038\/ni.1932","article-title":"IFI16 Is an Innate Immune Sensor for Intracellular DNA","volume":"11","author":"Unterholzner","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/ni.2091","article-title":"The Helicase DDX41 Senses Intracellular DNA Mediated by the Adaptor STING in Dendritic Cells","volume":"12","author":"Zhang","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41576-019-0151-1","article-title":"DNA Sensing by the cGAS\u2013STING Pathway in Health and Disease","volume":"20","author":"Motwani","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"29769","DOI":"10.1038\/s41598-024-81833-w","article-title":"Kaempferol Alleviates Rheumatoid Arthritis through Pyroptosis Based on Bioinformatics Analysis and Experimental Validation","volume":"14","author":"Ling","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1007\/s10753-014-9909-y","article-title":"Berberine Ameliorates Collagen-Induced Arthritis in Rats Associated with Anti-Inflammatory and Anti-Angiogenic Effects","volume":"37","author":"Wang","year":"2014","journal-title":"Inflammation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"108854","DOI":"10.1016\/j.intimp.2022.108854","article-title":"Gentiopicroside Attenuates Collagen-Induced Arthritis in Mice via Modulating the CD147\/P38\/NF-\u03baB Pathway","volume":"108","author":"Jia","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/art.20715","article-title":"Suppression of the Onset and Progression of Collagen-induced Arthritis by Chebulagic Acid Screened from a Natural Product Library","volume":"52","author":"Lee","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose Translation from Animal to Human Studies Revisited","volume":"22","author":"Nihal","year":"2008","journal-title":"FASEB J."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Van Miert, A.S.J.P.A.M., Bogaert, M.G., and Debackere, M. (1986). The Use in Animals of Drugs Licensed for Human Use Only. Comparative Veterinary Pharmacology, Toxicology and Theraphy, Springer.","DOI":"10.1007\/978-94-009-4153-3"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s00441-015-2194-8","article-title":"Adenovirus-Mediated Osteoprotegerin Ameliorates Cartilage Destruction by Inhibiting Proteoglycan Loss and Chondrocyte Apoptosis in Rats with Collagen-Induced Arthritis","volume":"362","author":"Feng","year":"2015","journal-title":"Cell Tissue Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.intimp.2014.12.012","article-title":"Celastrol Attenuates Bone Erosion in Collagen-Induced Arthritis Mice and Inhibits Osteoclast Differentiation and Function in RANKL-Induced RAW264.7","volume":"24","author":"Gan","year":"2015","journal-title":"Int. Immunopharmacol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/8\/1302\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:22:56Z","timestamp":1787199776000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/8\/1302"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":46,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ph19081302"],"URL":"https:\/\/doi.org\/10.3390\/ph19081302","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]}}}