Unlocking Myofibroblast Plasticity to Reverse Salivary Gland Fibrosis

Salivary gland (SG) fibrosis represents a critical pathological feature of exocrine hypofunction driven by the persistent activation of myofibroblasts (MFs). 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-such as mitochondrial metabolic reprogramming, store-operated calcium entry (SOCE) collapse, and persistent cGAS-STING innate immune sensing-are 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-ranging from small-molecule inhibitors (SB431542, decitabine) and biologics (rituximab) to traditional botanical formulations (Shengmai San) and stem cell-derived extracellular vesicles-that effectively attenuate scar formation and improve salivary flow rates in preclinical or clinical models. Ultimately, this review establishes a novel, etiology-driven "etiology-origin-pathway-target" matrix that shifts the paradigm from empirical anti-inflammatory management toward origin-specific precision therapeutics capable of reversing established salivary gland fibrosis.