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However, the translational gap between the convoluted in vivo regulatory networks governing these cells and the deployment of precise, disease-modifying interventions remains a formidable challenge. This review systematically examines current mechanistic evidence undergirding MF activation, survival, and its phenotypic reversal, focusing on restoring glandular function. We synthesize recent literature mapping in vivo canonical profibrotic signaling cascades, noncanonical crosstalks, and cellular heterogeneity within the injured exocrine stroma. Evidence underscores that the pathological tilt between profibrotic Smad3 and inhibitory Smad7 acts as a critical rheostat for MF differentiation across diverse etiologies. Beyond classical pathways, emerging mechanisms\u2014such as mitochondrial metabolic reprogramming, store-operated calcium entry (SOCE) collapse, and persistent cGAS-STING innate immune sensing\u2014are mechanically reinforced by extracellular matrix rigidity via a YAP\/TAZ mechanotransduction loop. These events, coupled with aberrant epigenetic imprinting, structurally lock the persistent MF phenotype and restrict cellular plasticity. Consequently, we evaluate targetable interventions\u2014ranging from small-molecule inhibitors (SB431542, decitabine) and biologics (rituximab) to traditional botanical formulations (Shengmai San) and stem cell\u2013derived extracellular vesicles\u2014that effectively attenuate scar formation and improve salivary flow rates in preclinical or clinical models. Ultimately, this review establishes a novel, etiology-driven \u201cetiology-origin-pathway-target\u201d matrix that shifts the paradigm from empirical anti-inflammatory management toward origin-specific precision therapeutics capable of reversing established salivary gland fibrosis.<\/jats:p>","DOI":"10.1177\/00220345261465355","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T05:56:30Z","timestamp":1785736590000},"page":"1515-1526","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Unlocking Myofibroblast Plasticity to Reverse Salivary Gland Fibrosis"],"prefix":"10.1177","volume":"105","author":[{"given":"S.","family":"Pan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine, Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology, Wuhan University, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.-N.","family":"Zhong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine, Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology, Wuhan University, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Peng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine, Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology, Wuhan University, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine, Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology, Wuhan University, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Kang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine, Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology, Wuhan University, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.","family":"Cao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine, Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology, Wuhan University, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine, Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology, Wuhan University, Wuhan, China"},{"name":"Department of Oral Radiology, School &amp; Hospital of Stomatology, Wuhan University, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4951-4241","authenticated-orcid":false,"given":"Y.","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine, Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology, Wuhan University, Wuhan, China"},{"name":"Department of Oral Radiology, School &amp; Hospital of Stomatology, Wuhan University, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,8,2]]},"reference":[{"key":"e_1_3_4_2_1","doi-asserted-by":"crossref","unstructured":"Altrieth AL et al. 2023. 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