Molecular endotyping in systemic lupus erythematosus: an integrative framework toward precision therapy.

Abstract

Systemic lupus erythematosus (SLE) is a clinically defined syndrome arising from heterogeneous and dynamically interacting molecular programs. Recent transcriptomic, single-cell, spatial, and functional studies have identified recurrent molecular states; however, published three-, five-, six-, and eight-group taxonomies are not directly interchangeable. In this review, the published evidence was synthesized within a pragmatic framework of four overlapping candidate programs: interferon/interferon-stimulated gene (IFN/ISG), B cell/plasmablast, neutrophil/neutrophil extracellular trap (NET), and an emerging immunometabolic program. Complement/immune-complex activation is considered a cross-cutting effector axis rather than a mutually exclusive endotype. The molecular endotype is defined operationally, and a distinction is made between pathway signatures, candidate endotypes, and clinically actionable endotypes. In this review, activity biomarkers, prognostic biomarkers, pharmacodynamic biomarkers, and predictive biomarkers are distinguished; the transcriptomic ISG-high states are distinguished from directly measurable type I IFN bioactivity; and the contributions of short-lived plasmablasts and long-lived plasma cells to autoantibody production are also examined. It should be emphasized that endotype assignment is time- and compartment-dependent and that blood signatures may not fully capture organ-specific disease, particularly lupus nephritis. Molecular endotyping in SLE should therefore be viewed as a research framework toward precision therapy rather than as a current treatment algorithm. Prospective biomarker-enriched trials and longitudinal multi-compartment profiling will be required to establish clinically actionable endotypes.