Defining PI3K Signaling as a Key Regulator of Molecular Heterogeneity and Inflammation in Glomerular Lupus Nephritis

Lupus nephritis (LN) is a critical manifestation in systemic lupus erythematosus. However, there has been little progress in treatment outcomes, and the discovery of robust and clinically relevant molecular subtypes would be informative for guiding stratified therapy for LN. Glomerular transcriptomic datasets of LN were obtained from publicly repositories. We investigate the molecular heterogeneity of LN by analyzing renal glomerular transcriptomic data from 135 patients with LN using integrated optimal algorithms and propose a refined two-molecular subtype scheme for LN (designated GC1 and GC2). GC1 represents an active form of LN enriched by IFN signaling pathways, Fc receptor-mediated signals, and neutrophil activation-associated processes. In contrast, GC2 is a subset characterized by class A/1 (rhodopsin-like) and B cell (BC) receptor signaling pathways. The communication probability by receptor-ligand pairs is highly scored between BCs, CD4+ T cells and macrophages/monocytes. Proteinuria and renal insufficiency were more significant in GC1. We identified PIK3R2 as a hidden regulator in the disease module, and inhibition of PI3K subunits showed promising efficacy in counteracting altered molecular signatures in an active state of LN. The proposed two-molecular subtype scheme offers novel insights into the divergent mechanistic features of LN and represents a critical step toward precision medicine for LN.