Linderalactone mitigates diabetic renal injury by inhibiting macrophage inflammation via the Dectin1/Syk/CARD9/IRF5/NF-κB pathway.

Inflammation plays an essential role in the pathogenesis of diabetic nephropathy (DN). Linderalactone (LNL), as a natural sesquiterpene lactone, has been discovered to have anti-inflammatory activation. However, the effects of linderalactone on diabetes-associated renal damage remain unclear. This study investigated the effects of LNL on renal function and inflammation in diabetic mice. Renal function, collagen deposition, and fibrosis were assessed. RNA-sequencing was performed to identify molecular pathways affected by LNL. The Dectin1-related pathway was analyzed in kidney tissues and RAW264.7 cells. Dectin1-deficient and Dectin1-overexpressing models were used to confirm the mechanism of LNL. LNL improved renal function, reduced collagen deposition and fibrosis in diabetic mice without affecting blood glucose levels. RNA-sequencing revealed that LNL primarily impacted the Dectin1 pathway. It inhibited the Dectin1/Syk/CARD9/IRF5/NF-κB pathway, reduced macrophage and neutrophil infiltration, and suppressed inflammatory cytokine expression. Dectin1 knockdown mimicked these effects, while Dectin1 overexpression reversed them. LNL alleviates DN via suppression of macrophage inflammation by mediating the Dectin1/Syk/CARD9/IRF5/NF-κB signaling pathway, highlighting its potential as a therapeutic agent for diabetes-associated renal injury.