S-methylmethionine ameliorates renal injury in diabetic mice by modulating macrophage inflammaging via ERK/NF-κb signaling pathway.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, yet current therapeutic strategies remain insufficient to halt its progression. Emerging evidence suggests that macrophage-mediated inflammaging is a key pathogenic mechanism underlying diabetic renal injury, but effective targeted interventions are still limited. In this study, we identify S-Methylmethionine (SMM) as a candidate therapeutic compound capable of modulating macrophage inflammaging, and systematically evaluate its protective potential. In streptozotocin-induced diabetic mice, SMM markedly improved renal function in a dose-dependent manner, alleviating glomerular hypertrophy, mesangial expansion, and fibrosis, accompanied by reductions in biomarkers of kidney injury. The transcriptomic analysis of kidney tissues from patients with DKD revealed enrichment of aging- and inflammation-related pathways, which were effectively suppressed by SMM. SMM attenuated macrophage inflammaging by inhibiting proinflammatory cytokines release, reducing the expression of senescence-associated proteins, and promoting a shift in macrophage polarization toward a reparative phenotype. SMM also blocked phosphorylation and nuclear translocation of ERK and NF-κB p65, thereby repressing downstream inflammatory and senescence gene expression programs. Collectively, these findings establish SMM as a novel modulator of macrophage inflammaging and highlight its therapeutic potential for the treatment of DKD.