Abstract
Primary membranous nephropathy (PMN) is a prevalent renal disorder characterized by immune-mediated damage to the glomerular basement membrane, with recent studies highlighting the significant role of pyroptosis in its progression. In this study, we investigate the molecular mechanisms underlying PMN, focusing on the role of Tumor necrosis factor receptor-associated factor 6 (TRAF6) in promoting disease advancement. Specifically, we examine how TRAF6 facilitates PMN progression by inducing the ubiquitination of Transforming growth factor-beta-activated kinase 1 (TAK1), which in turn activates the Gasdermin D (GSDMD)/Caspase-1 axis, leading to podocyte pyroptosis. Utilizing transcriptomic data from the gene expression omnibus database, we identified key regulatory factors involved in pyroptosis and validated these findings through the establishment of a C3a-induced podocyte injury model and a Sprague-Dawley (SD) rat model of PMN. Our findings reveal that TRAF6 is significantly upregulated in PMN, and its interaction with TAK1 is crucial for the activation of the GSDMD/Caspase-1 axis, ultimately driving podocyte pyroptosis. Further biochemical and molecular analyses confirmed the pivotal role of the TRAF6/TAK1 signaling pathway in the pathogenesis of PMN. These results underscore the importance of TRAF6-mediated signaling in the progression of PMN and suggest that targeting the TRAF6/TAK1/GSDMD/Caspase-1 axis may offer a novel therapeutic strategy for the treatment of this debilitating renal disease.