IRF8 transcriptionally drives NAIP to promote NLRP3/NLRC4 inflammasome-mediated renal tubular pyroptosis in diabetic kidney disease

Renal tubular pyroptosis is a key driver of inflammation and fibrosis in diabetic kidney disease (DKD), yet the contribution of the NAIP-NLRC4 inflammasome arm and its upstream transcriptional control have remained undefined. This study investigated whether NAIP causally promotes tubular pyroptosis in DKD and identified the transcription factor responsible for its induction.

NAIP and IRF8 expression were examined across Nephroseq DKD cohorts and correlated with renal function. Naip1-6^Δ/Δ and Irf8-knockout mice, together with high glucose-treated HK-2 cells, were used to assess pyroptosis and fibrosis. IRF8 binding to the NAIP promoter was tested by JASPAR prediction, chromatin immunoprecipitation and dual-luciferase reporter assays, and causality was confirmed by NAIP knockdown/overexpression and by AAV9-mediated NAIP restoration in Irf8-knockout mice.

NAIP was upregulated in diabetic renal tissue and correlated with declining renal function. Naip deletion attenuated proteinuria, fibrosis and NLRP3/NLRC4-dependent pyroptosis in STZ-diabetic mice, and NAIP knockdown reproduced this protection in high glucose-treated HK-2 cells. IRF8 was concurrently induced under hyperglycemia and correlated with NAIP expression; IRF8 bound directly to the NAIP promoter and transcriptionally activated it. NAIP overexpression abolished the protective effects of IRF8 silencing in vitro, and AAV9-mediated NAIP restoration similarly reversed the renoprotection conferred by Irf8 knockout in vivo.

IRF8 transcriptionally drives NAIP expression to promote tubular inflammasome activation, pyroptosis and fibrosis in DKD, establishing the IRF8-NAIP axis as a novel mechanistic link and candidate therapeutic target in diabetic kidney disease.