METTL3-targeted intervention on nuclear factors RORA/RORγt suppresses pathogenic T helper 17 cell differentiation and alleviates kidney damage in lupus nephritis.

Abnormal differentiation of T helper 17 (Th17) cells is an important mechanism underlying lupus nephritis (LN) pathogenesis. However, its driving mechanism remains unclear. Modification of m6A, the most dominant RNA modification, is a novel mechanism for regulating cell phenotypes and functions, with methyltransferase-like 3 (METTL3) being an important methyltransferase. Nonetheless, whether m6A modification participates in the regulation of Th17 cell differentiation in patients with LN has not been reported. Our study investigates the effect of targeting METTL3 on Th17 cell infiltration, assesses its potential therapeutic role in LN, and further clarifies underlying mechanisms. Murine LN models (MRL/lpr, pristane-induced BALB/c) received STM2457 or standard drugs. Tissues, blood, and urine were collected after eight-week regimens. Blood and kidney needle biopsy specimens were collected from patients with LN along with control individuals. Multi-omic analyses along with cellular, molecular, and imaging assays assessed immunopathology and therapeutic effects. The infiltration of CD4+ T cells and pathogenic Th17 cells in the kidneys of patients with LN and MRL/lpr mice were higher than those in control individuals, accompanied by high METTL3 expression. METTL3 upregulation promoted differentiation of Th17 cells and mediated kidney injury. Mechanistic investigations revealed that METTL3 promotes pathogenic Th17 cell differentiation via two pathways. First, by increasing m6A modification of nuclear factor RAR-related orphan receptor (RORA) transcripts, thereby stabilizing them and enhancing RORA expression. Second, by augmenting RAR-related orphan receptor C (RORC) expression through elevating Smad2 and STAT3 phosphorylation levels in an m6A-independent manner. Furthermore, specific inhibition of METTL3 in CD4+ T cells can suppress the differentiation of pathogenic Th17 cells, thereby blocking the development of nephritis and alleviating kidney damage. METTL3 may serve as a new therapeutic target for precise LN treatment.