Mitigation of renal tubular injury by SIRT6 may improve individual outcomes in diabetic kidney disease-potential mechanisms involving epigenetic repression of inflammatory responses

• Spatially resolved transcriptomics reveals SIRT6 downregulation in tubular epithelial cells (TECs) as a hallmark of diabetic kidney disease (DKD), correlating with disease severity. • SIRT6 epigenetically silences Nlrp3 transcription by deacetylating H3K9ac, thereby suppressing NLRP3 inflammasome activation and mitigating tubular injury. • TEC-specific Sirt6 deletion exacerbates renal dysfunction in DKD models, whereas its overexpression confers protection, establishing a causal role in disease progression. • Pharmacological SIRT6 activation attenuates DKD pathology, highlighting its therapeutic potential for tubulointerstitial injury in diabetes. Progressive tubulointerstitial injury plays a critical role in the progression of diabetic kidney disease (DKD), but the epigenetic mechanisms driving this process remain largely unclear. This study aimed to investigate the role of the histone deacetylase SIRT6 in renal tubular epithelial cells (TECs) during DKD progression and to explore its potential as a therapeutic target. We employed digital spatial profiling (DSP) to perform spatially resolved mRNA quantification in proximal renal tubular tissue from DKD patients. Additionally, we used genetic and pharmacological approaches in DKD mouse models to assess the effects of SIRT6 deficiency or overexpression on renal injury. Mechanistic studies included RNA-sequencing (RNA-seq) and Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, which to identify SIRT6-regulated genes and epigenetic modifications. Our findings revealed a significant reduction of SIRT6 in TECs from DKD patients, with its expression inversely correlating with disease severity. TEC-specific SIRT6 deficiency worsened renal injury and proteinuria in DKD mice, whereas SIRT6 overexpression or pharmacological activation provided renoprotection. Mechanistically, SIRT6 directly repressed Nlrp3 transcription by deacetylating histone 3 lysine 9 acetylation (H3K9ac), thereby inhibiting NLRP3 inflammasome activation and subsequent TEC injury. These findings highlight SIRT6 as a protective epigenetic factor in DKD and suggest its potential utility for disease stratification, early therapeutic intervention, and precision medicine.