Sphinganine as a potentially relevant metabolite in pulmonary involvement of primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and frequent extraglandular manifestations, with pulmonary involvement being the most prevalent. However, the mechanisms underlying pulmonary involvement remain unclear, and the role of shared metabolic disturbances in disease pathogenesis is yet to be fully elucidated. Bibliometric analyses have highlighted interstitial lung disease as a key research focus in pSS. In this study, we used an experimental SS mouse model to perform pseudotargeted sphingolipidomics on the salivary glands and lungs. Sphinganine (Sa) was identified as a key metabolite through machine learning-based screening. In vivo experiments demonstrated that administration of Sa aggravated salivary gland injury and pulmonary fibrosis in the experimental SS group. Further in vitro studies revealed that Sa activates the endoplasmic reticulum stress pathway, leading to A253 cell damage and upregulation of fibrosis markers in NIH3T3 fibroblasts. Chemoproteomic analysis revealed that Sa directly binds to the nonmuscle myosin heavy chain IIA (Myh9) and promotes its expression. Pharmacological inhibition of Myh9 restored aquaporin-5 (AQP5) expression in A253 cells and reduced fibronectin and alpha-smooth muscle actin levels in NIH3T3 cells. Collectively, this study indicates that Sa, as a shared regulatory metabolite between the salivary gland and lung, appears to be implicated in the ATF6-Myh9 signaling axis and may contribute to pSS-related pulmonary injury. Nevertheless, this relationship warrants further validation in future studies. In parallel, it proposes a novel strategy for identifying common metabolic biomarkers across affected organs in autoimmune diseases.