Sjögren's syndrome (SS) is a chronic systemic autoimmune disease characterized by the main clinical manifestation of oral and ocular dryness, predominantly affecting middle-aged and elderly women. As the most commonly affected target organs in SS, pathological changes in the salivary glands (SGs) and their underlying mechanisms are of great significance for understanding the disease progression. Recent studies have revealed that a dynamic imbalance of the extracellular matrix (ECM) in the SGs plays a crucial role in the pathogenesis of SS. Dysregulation of matrix metalloproteinases (MMPs) and the fibrotic processes they mediate constitute the core pathological changes. These alterations intertwine with local chronic inflammatory responses, cellular senescence, and hyperosmolarity, collectively leading to the destruction of the SG parenchymal structure and progressive loss of secretory function, significantly impairing the patients' quality of life. However, research on the pathological mechanisms of the SG ECM remains insufficient, and there are currently no specific therapeutic interventions targeting ECM alterations in clinical practice. This review systematically elucidates the characteristics of pathological and physiological changes in the SG ECM in SS and thoroughly explores novel therapeutic strategies based on ECM regulation, as well as their clinical application prospects. Recent studies have revealed that a dynamic imbalance of the extracellular matrix (ECM) in the SGs plays a crucial role in the pathogenesis of SS. Dysregulation of matrix metalloproteinases (MMPs) and the fibrotic processes they mediate constitute the core pathological changes. These alterations intertwine with local chronic inflammatory responses, cellular senescence, and hyperosmolarity, collectively leading to the destruction of the SG parenchymal structure and progressive loss of secretory function, significantly impairing the patients’ quality of life. The disease predominantly affects middle-aged and elderly women and is characterized by impaired exocrine gland function, lymphocyte infiltration, and production of various autoantibodies [ 1 ]. The exact pathogenesis of SS remains unclear. Current treatment strategies primarily rely on artificial saliva and tears to alleviate dryness, along with corticosteroids, disease-modifying antirheumatic drugs, and biologics to suppress inflammation and modulate the immune function. However, some patients respond poorly to existing treatments, and the long-term use of immunosuppressants may increase the risk of infection. During early embryonic development, ECM remodeling is closely related to the branching morphology of the SGs [ 12 ]. As the SG matures, the ECM components are continuously renewed to maintain normal gland structure and function. However, during aging, collagen deposition increases in the SGs, accelerating fibrosis and leading to progressive gland dysfunction [ 13 ]. Although fibrosis is a natural outcome of SG aging, SS significantly accelerates this process [ 14 ]. Dysregulation of matrix metalloproteinases (MMPs) and SG fibrosis are key events in SS that disrupt ECM homeostasis and exacerbate glandular dysfunction ( Figure 1 ). Research on epigenetic regulation-mediated MMP dysregulation mechanisms in SGs remains unexplored. Elucidating this mechanism will not only clarify the pathological basis of SS but also provide crucial direction for developing novel diagnostic biomarkers and precise therapeutic targets. 3.1.5. Impact of MMP Dysregulation on SG Structure and Function MMPs disrupt the normal SG structure and function through various mechanisms in SS. MMPs degrade key ECM components that directly damage the SG structure. Normal SGs exhibit intact nuclear polarity, organized microvilli, continuous basement membrane, and balanced secretory granule dynamics within a structured ECM. In contrast, diseased glands display disrupted nuclear polarity, disorganized microvilli, increased apoptosis, aberrant accumulation or depletion of secretory granules, fragmented basement membrane, and ECM remodeling characterized by collagen deposition and laminin degradation. These structural defects impair secretory function, exacerbate inflammation–fibrosis crosstalk, and ultimately lead to irreversible gland dysfunction and xerostomia. This deficiency in the ECM microenvironment leads to organoids’ inability to accurately replicate the highly sophisticated tissue architectures of in vivo glands—particularly regarding vascularization, neural networks, and complete ductal systems—while their secretory functions and responsiveness to physiological stimuli also significantly deviate from those of native glands. Consequently, exploring and integrating biomaterials that better mimic natural SG ECM properties (e.g., SG-derived dECM or its functionalized derivatives) as culture scaffolds or microenvironmental components represents a key strategy to overcome these limitations. This “imaging + serology + pathology” multidimensional evaluation model can effectively identify patients at risk for advanced fibrosis, providing critical timing for implementing early targeted interventions. 5. Conclusions In SS, the imbalance of the SG ECM—particularly the dysregulated expression of MMPs and the fibrotic process—has become a central link in understanding the disease’s pathological mechanism. This process interacts closely with chronic Stem cell therapy possesses significant immunomodulatory and tissue repair capabilities, but its efficacy is considerably influenced by the timing of transplantation and the status of the local microenvironment. Furthermore, while tissue engineering approaches offer new possibilities for SG functional regeneration, technical bottlenecks remain in replicating the complex structure and function of the native gland. Future effective ECM-targeted therapies will rely on the integration of early intervention and combined treatment strategies.