BiomiX-Driven Multi-Omics Integration of PRECISESADS Data Reveals Lysophosphatidic Acid and Metabolic Pathway Signatures in B Cells and Immune Macroenvironment in Sjögren’s Disease

Objective Sjögren’s disease (SjD) is a systemic autoimmune disorder characterized by lymphocytic infiltration of exocrine glands, resulting in xerostomia, keratoconjunctivitis sicca, fatigue, arthralgia, and systemic organ involvement. This study aimed to characterize the metabolic and immune dysregulation of SjD using a multi-omics approach, focusing on the metabolic environment and B-cell transcriptomic responses. Methods Transcriptomic, methylomic, and metabolomic datasets from whole blood, plasma, and urine of 293 SjD patients and 508 controls were analyzed from the PRECISESADS study. B-cell transcriptomes were included to link systemic metabolic alterations to cell-intrinsic immune programs. Multi-omics factor analysis (MOFA) was used to integrate data and identify discriminant molecular drivers. Results Multi-omics integration revealed metabolic rewiring involving the urea cycle, glutamine/arginine metabolism, and NAD⁺ depletion linked to interferon signaling. Among the strongest contributors, plasma lysophosphatidic acids (LPA) emerged as key discriminants associated with interferon-driven activation. B-cell transcriptomes showed upregulation of LPA-related genes (CERS6, INPP1, TRIP6), and its receptor LPAR6. Importantly, in this study LPAR6 protein expression was confirmed in B cells for the first time. Secondary findings included alterations in sphingosine-1-phosphate (S1P) metabolism, suggesting a broader lysophospholipid signaling axis. Conclusions This study identifies the LPA–LPAR6 signaling axis as a potential metabolic driver of B-cell activation and interferon-associated inflammation in SjD, highlighting a previously unrecognized immunometabolic pathway. These findings highlight LPA–LPAR6 as a candidate target for therapeutic modulation in SjD, while also implicating S1P signaling as a complementary regulatory mechanism.