The m6A reader IGF2BP2 promotes proinflammatory signaling in Lupus nephritis by recognizing STAT1 m6A modifications.

Characterized by renal inflammation and structural damage, lupus nephritis (LN) is a severe and often debilitating complication of systemic lupus erythematosus. The dynamic regulation of RNA processing, stability, and translation by N6-methyladenosine (m6A) modification has been implicated in the pathophysiology of LN. As an m6A reader, insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) plays a crucial role in the pathogenesis of various kidney diseases, yet its precise function in LN remains unclear. IGF2BP2 expression was measured in kidney specimens from LN patients and MRL/LPR mice. MRL/lpr mice were administered IGF2BP2 short hairpin RNA adeno-associated viral vectors, followed by evaluation of proteinuria, renal function, and histology. In vitro experiments employed lipopolysaccharide (LPS) stimulation of human kidney tubular epithelial cells (HK-2) to simulate LN inflammatory responses and further investigated the mechanism of IGF2BP2. Molecular interactions were validated via RNA immunoprecipitation and luciferase reporter assays. IGF2BP2 expression is significantly upregulated in LN and positively correlated with proinflammatory factor levels. Knockdown of IGF2BP2 significantly improved renal injury and alleviated renal inflammatory responses in MRL/LPR mice, as well as reduced LPS-induced inflammatory responses in HK-2 cells. Mechanistically, under LN pathological conditions, IGF2BP2 recognized m6A modifications on signal transducer and activator of transcription 1 (STAT1) mRNA and enhanced its stability, leading to the activation of proinflammatory signaling, exacerbation of renal inflammation, and ultimately renal injury. The m6A reader IGF2BP2 promotes proinflammatory signaling in LN by recognizing m6A-modified STAT1 mRNA. Targeting the IGF2BP2-STAT1 axis may represent a potential therapeutic strategy to ameliorate renal inflammatory responses in LN.