Serum glycerophospholipid remodeling and reduced acyl-chain unsaturation define clinical heterogeneity in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Patients with SLE display a complex lipid metabolism dysregulation that remains poorly understood. Using lipidomic profiling of serum samples from 121 SLE patients and 106 matched healthy controls, we observed a distinct lipid signature characterized by elevated glycerophospholipids (GPLs) and reduced free fatty acids (FFAs) and lysophospholipids (LPLs). This profile, along with the downregulation of key phospholipases (PLA1, iPLA2), is consistent with altered GPL turnover. Polyunsaturated fatty acid (PUFA) oxidation products exhibited selective remodeling, with some species increased and others decreased, reflecting disturbed redox-lipid balance. GPL unsaturation analysis revealed reduced acyl-chain unsaturation in SLE, with the most pronounced change observed in the putatively assigned sn -1 acyl chain and polyunsaturated PC species. Hierarchical clustering based on GPL unsaturation separated SLE patients into high (HGPU) and low (LGPU) GPL unsaturation groups. The LGPU subgroup displayed higher reactive oxygen species levels, elevated anti-phospholipid antibody titers, increased SLE disease activity scores, and more pronounced clinical manifestations. Our study identifies a GPL metabolism abnormality and provides a framework for SLE stratification based on GPL unsaturation, offering new insights for the development of precision medicine.