Systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) frequently coexist as overlapping autoimmune conditions, yet the molecular mechanisms that drive the development of secondary Sjögren’s syndrome in SLE patients (SLE-pSS) remain poorly defined. While recent studies have identified megakaryocyte (MK) expansion as a shared feature across autoimmune diseases, the upstream hematopoietic events governing this phenomenon and their contribution to glandular involvement have not been elucidated.

We performed comprehensive transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from 30 SLE-pSS overlap patients, 30 SLE alone patients, and 20 healthy controls using RNA sequencing. Differential gene expression analysis, functional enrichment (GO/KEGG), and protein-protein interaction network construction were conducted to identify core molecular signatures. Key findings were integrated with clinical parameters, including disease activity scores (SLEDAI, ESSDAI), sicca symptom assessments, and routine blood counts.

We identified PRDM16 as a central hub gene significantly upregulated in SLE-pSS patients compared to SLE alone (fold change > 2.5, p < 0.001), accompanied by coordinated activation of megakaryocyte-lineage transcription factors (GATA1, TAL1, GFI1B) and robust enrichment of myeloid differentiation pathways. Concurrently, erythroid genes (HBG1, AHSP) and eosinophil markers (CLC) were markedly downregulated, indicating a myeloid-biased hematopoietic output with concurrent suppression of erythroid and granulocytic lineages. Mechanistically, PRDM16-driven myeloid skewing was associated with expansion of immunogenic MKs expressing HLA-F and inflammatory mediators (PTGS2, IL6), alongside accumulation of T-cell chemoattractants (CCL25). Notably, salivary gland epithelial vulnerability was reflected by coordinated downregulation of structural integrity genes (KRT18, CLDN6) and activation of fibrotic remodeling programs (COL5A1, WNT2B). Correlation analyses revealed that PRDM16 expression levels negatively correlated with hemoglobin (r = -0.52, p < 0.01) and platelet counts (r = -0.48, p < 0.01), and positively correlated with ESSDAI scores (r = 0.61, p < 0.001) and sicca symptom severity.

SLE-associated Sjögren’s syndrome is characterized by PRDM16-driven hematopoietic remodeling toward the myeloid/megakaryocyte lineage, which generates immunogenic cells capable of targeting vulnerable glandular epithelium. This study establishes a novel paradigm linking bone marrow lineage bias to organ-specific autoimmunity, providing potential diagnostic biomarkers (PRDM16, APOA1) and therapeutic targets (IL6, PTGS2, PRDM16) for patients with overlapping SLE and pSS.