Sjögren’s disease (SjD) is a chronic systemic autoimmune disorder characterized by focal lymphocytic infiltration, progressive salivary gland dysfunction, and severe dryness. Current treatments remain largely palliative, highlighting the critical need for novel therapeutic targets. Although the cellular mechanisms are increasingly understood, an integrated view of how metabolic pathways and cellular interactions converge remains lacking. This review aims to propose a comprehensive conceptual framework in which metabolic reprogramming serves as a central pathogenic hub linking persistent immune activation and progressive epithelial damage within the complex SjD microenvironment.

 We systematically synthesized current literature encompassing in vitro studies, animal models, and human multi-omics data to evaluate the characteristic metabolic alterations in key pathogenic cell subsets, including CD4+ T cells, B cells, macrophages, and salivary gland epithelial cells (SGECs). Our analysis specifically focused on the mechanistic roles of major cellular energy pathways—namely aerobic glycolysis, oxidative phosphorylation, lipid metabolism, and iron-dependent lipid peroxidation (ferroptosis)—in driving cellular dysfunction and intricate inter-cellular communication. 

Accumulating evidence indicates that metabolic reprogramming orchestrates a self-amplifying immune-epithelial vicious cycle. Specifically, hyperactive glycolysis and mTOR signaling enable infiltrating effector T cells and B cells to sustain robust proliferation and massive autoantibody production. Concurrently, these highly active immune cells release pro-inflammatory cytokines and altered metabolites that render adjacent SGECs highly vulnerable to metabolic stress and ferroptotic cell death. Crucially, recent breakthroughs utilizing advanced spatial transcriptomics and spatial metabolomics reveal that this metabolic rewiring is highly spatially organized rather than uniformly distributed across the tissue. Specific metabolic signatures are strictly compartmentalized; for instance, the focal enrichment of phosphatidylserine (PS(36:1)) and upregulated phospholipid metabolism are exclusively localized within the dense lymphocytic foci. In stark contrast, the surrounding damaged epithelial cells exhibit distinctly different metabolic profiles characterized by severe lipid reactive oxygen species (ROS) accumulation. 

Metabolic reprogramming is a fundamental driving force, rather than a mere secondary consequence, of SjD pathogenesis. The newly identified spatial metabolic heterogeneity profoundly challenges the conventional view of a uniformly inflamed glandular tissue. This spatial compartmentalization provides vital new insights into the focal nature of SjD pathology and uncovers precisely localized, metabolism-based vulnerabilities, paving the way for the development of novel, targeted immunometabolic therapeutic interventions.