Mechanism of FABP4-driven macrophage pyroptosis in promoting renal tubular epithelial-mesenchymal transition of diabetic kidney disease in mice.

Macrophage-mediated inflammatory responses play a critical role in the onset and progression of diabetic kidney disease (DKD), yet the underlying molecular mechanisms remain incompletely understood. In this study, we found that the expression of fatty acid-binding protein 4 (FABP4) was significantly elevated in renal tissues from patients with diabetic kidney disease. Both in vivo and in vitro experiments further demonstrated that under high-glucose and high-lipid conditions, FABP4 activated macrophage-associated inflammation and promoted epithelial-mesenchymal transition (EMT) in HK-2 cells. Mechanistically, FABP4 transported saturated fatty acids into macrophages, activating the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which subsequently triggered caspase-1/gasdermin D (GSDMD)-mediated pyroptosis and the maturation and release of IL-1β. These inflammatory signals ultimately regulated the EMT process in renal tubular epithelial cells and enhanced the migratory ability of HK-2 cells. Collectively, FABP4 in macrophages is a key regulator of the NLRP3/IL-1β signaling axis, promotes the progression of DKD in mice, and represents a potential molecular target for the treatment of this disease.