Long non-coding RNA NEAT1 mediated lupus nephritis induced podocytes pyroptosis through DNMT1-STING axis.

Lupus nephritis (LN), a severe complication of systemic lupus erythematosus, is characterized by podocyte injury mediated through autoantibody deposition, yet the underlying mechanisms remain incompletely understood. This study investigated the role of long non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) in podocyte pyroptosis and its interaction with the stimulator of interferon genes (STING) pathway. Using peripheral blood mononuclear cells (PBMCs) and IgG isolated from 25 LN patients and 20 healthy controls, we found NEAT1 expression was significantly elevated in LN patient PBMCs and confirmed this in MRL/lpr mice. In vitro experiments demonstrated that LN-IgG treatment induced dose-dependent podocyte pyroptosis in human podocytes, an effect enhanced by NEAT1 overexpression and suppressed by its knockdown. Further analysis revealed STING expression correlated with NEAT1 levels, and STING knockdown attenuated pyroptosis. Mechanistically, we identified that NEAT1 bound directly to dysregulation of DNA methyltransferase 1 (DNMT1), with RNA immunoprecipitation (RIP)-qPCR showing a 4.3-fold enrichment (p < 0.001), and observed significant DNMT1 upregulation in LN. Functional studies demonstrated that DNMT1 overexpression counteracted NEAT1's regulatory effect on STING, establishing the NEAT1/DNMT1/STING signaling axis as a crucial regulator of podocyte pyroptosis in LN. These findings identify this novel signaling axis as a promising therapeutic target for antibody-mediated glomerular injury.