Abstract

Chronic hyperglycemia-induced inflammation promotes structural remodeling and dysfunction in the kidney and heart, ultimately leading to diabetic cardiorenal complications. The abnormal activation of the myeloid differentiation primary response gene 88 (MyD88)-dependent signaling pathway plays a critical role in this process. This study aimed to evaluate the therapeutic effects and underlying mechanisms of a novel small-molecule MyD88 inhibitor, A5S, in diabetic cardiorenal complications. We established a streptozotocin (STZ)-induced type 1 diabetes mouse model and administered A5S (10 or 20 mg/kg) for 8 weeks. Renal and cardiac function, as well as tissue pathology, were assessed. RNA sequencing and molecular biology experiments were performed to elucidate potential mechanisms. A5S treatment significantly improved kidney function, reduced glomerulosclerosis and fibrosis, and alleviated myocardial hypertrophy and collagen deposition. Mechanistically, A5S blocked the toll-like receptor 4 (TLR4)–MyD88 interaction and inhibited the transforming growth factor-β-activated kinase 1 (TAK1)/mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) inflammatory pathway, thereby reducing macrophage infiltration and downregulating the expression of pro-inflammatory cytokines ( Tnfa , Il1b , and Il23 ) and chemotactic factors ( Cxcl1 and Csf3 ). Furthermore, cell–cell crosstalk assays demonstrated that A5S prevented macrophage-induced renal mesangial cell fibrosis and cardiomyocyte hypertrophy. These findings validated the protective effects of A5S against inflammation-driven diabetic cardiorenal complications and highlighted its potential as a drug candidate for targeting MyD88 in anti-inflammatory therapy.