{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T05:14:28Z","timestamp":1788671668963,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82174041"],"award-info":[{"award-number":["82174041"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81771089"],"award-info":[{"award-number":["81771089"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Shanghai Municipal Science and Technology Project","award":["22ZR1437400"],"award-info":[{"award-number":["22ZR1437400"]}]},{"name":"Biological Sample Bank Project of Ninth People\u2019s Hospital affiliated with Shanghai Jiao Tong University School of Medicine","award":["YBKB202107"],"award-info":[{"award-number":["YBKB202107"]}]},{"name":"Biological Sample Bank Project of Ninth People\u2019s Hospital affiliated with Shanghai Jiao Tong University School of Medicine","award":["YBYB202212"],"award-info":[{"award-number":["YBYB202212"]}]},{"award":["YBKB202107"],"award-info":[{"award-number":["YBKB202107"]}],"id":[{"id":"https:\/\/ror.org\/0220qvk04","id-type":"ROR","asserted-by":"publisher"}]},{"award":["YBYB202212"],"award-info":[{"award-number":["YBYB202212"]}],"id":[{"id":"https:\/\/ror.org\/0220qvk04","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Sj\u00f6gren\u2019s Syndrome (SS) is an autoimmune disorder with impaired exocrine gland function. Its pathogenesis remains elusive, but aberrant innate\/adaptive immunity and dysregulated interferon signaling are core features. Current SS research lacks exploration of innate immune mechanisms and therapeutic targets. Phloretin, a natural dihydrochalcone derivative, inhibits excessive innate immune activation, yet its role and mechanism in SS remain unreported. Methods: This study aimed to explore the therapeutic efficacy of phloretin against Sj\u00f6gren\u2019s syndrome (SS) and elucidate the regulatory mechanism underlying its effects on dendritic cells (DCs) and the Stimulator of Interferon Genes (STING)-driven innate immune cascade. Clinical specimens were utilized to analyze DC infiltration and STING expression in the labial glands of SS patients. In vivo experiments were conducted on NOD\/Ltj SS mice with phloretin treatment, using hydroxychloroquine as a positive control. For in vitro studies, DCs were stimulated with poly I:C to verify the functional effects of phloretin and its regulatory role in the STING\/TANK-binding kinase 1 (TBK1)\/Interferon Regulatory Factor 3 (IRF3) signaling. Salivary secretion, glandular inflammatory responses, and systemic immune overactivation were evaluated in SS mice. In poly I:C-stimulated DCs, cell activation, migration, and co-stimulatory molecule expression were measured. The regulatory effects of phloretin on the STING signaling cascade and STING ubiquitin-mediated degradation were examined by Western blotting. Phloretin, initially identified as a candidate compound via virtual screening, was subjected to thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and molecular dynamics simulation (MD) for direct binding verification with STING. The STING overexpression rescue experiment further corroborates that phloretin modulates innate immune responses in a STING-dependent manner. Results: Clinical results revealed obvious infiltration of CD11c+STING+ DCs and CD11c+p-TBK1+ DCs in labial gland lesions of SS patients. In NOD\/Ltj SS mice, phloretin treatment recovered salivary secretion, relieved glandular inflammatory injury, and restrained excessive activation of innate and adaptive immune responses, showing comparable therapeutic effects compared with hydroxychloroquine. In vitro experiments confirmed that phloretin could alleviate poly I:C-induced abnormal activation and migration of DCs, as well as reduce the expression of co-stimulatory molecules. Mechanistically, phloretin was found to interfere with the STING signaling cascade, alter the ubiquitination level of STING protein, and further inhibit the abnormal activation of DCs, which may contribute to its protective effects against Sj\u00f6gren\u2019s syndrome. Notably, results from MD, CETSA and DARTS collectively validate the interaction between phloretin and STING protein, providing solid molecular-level evidence for its regulatory effect on STING signaling transduction. Conclusions: DCs and STING-driven innate immunity critically contribute to SS progression. Phloretin effectively ameliorates SS-related immune disorders by restraining DC overactivation and STING signaling, supporting it as a promising candidate agent for SS treatment.<\/jats:p>","DOI":"10.3390\/ph19091398","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T12:20:19Z","timestamp":1788524419000},"page":"1398","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phloretin Modulates STING Ubiquitination Degradation to Restrain Dendritic Cell Overactivation and Alleviate Sj\u00f6gren\u2019s Syndrome"],"prefix":"10.3390","volume":"19","author":[{"given":"Tianle","family":"Zhan","sequence":"first","affiliation":[{"name":"Department of Oral Surgery, Shanghai Ninth People\u2019s Hospital, School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai 200011, China"},{"name":"National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, No. 639, Zhizaoju Rd, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4351-1701","authenticated-orcid":false,"given":"Haoran","family":"Chen","sequence":"additional","affiliation":[{"name":"National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, No. 639, Zhizaoju Rd, Shanghai 200011, China"},{"name":"Departmentof Interventional Therapy, Shanghai Ninth People\u2019s Hospital, School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Jian","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Medical School, Nantong University, No. 19 Qixiu Road, Nantong 226007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Chuangqi","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Oral Surgery, Shanghai Ninth People\u2019s Hospital, School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai 200011, China"},{"name":"National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, No. 639, Zhizaoju Rd, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1146\/annurev-pathol-012513-104728","article-title":"Sj\u00f6gren\u2019s syndrome","volume":"9","author":"Mavragani","year":"2014","journal-title":"Annu. 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