Dual Phosphorylation of STAT1 at Y701/S727 by TNFα Drives AIM2-Mediated PANoptosis of Renal Tubular Epithelial Cells and Fibrotic Progression in Renal Allografts

experiments, this work demonstrates that in the context of chronic inflammation, tumor necrosis factor-alpha (TNF-α) modulates signal transducer and activator of transcription 1 (STAT1) through dual phosphorylation. This process directly induces tyrosine 701 phosphorylation and activates serine 727 phosphorylation via the p38 MAPK pathway. Phosphorylated STAT1 subsequently upregulates the PANoptosome sensor absent in melanoma 2 (AIM2), driving PANoptosis in renal tubular epithelial cells. This mechanism further exacerbates interstitial fibrosis by promoting the paracrine secretion of interleukin-6 and transforming growth factor-beta, which induces epithelial-mesenchymal transition (EMT) in adjacent tubular cells. These findings represent the first demonstration of the TNF-α/STAT1/AIM2 axis in triggering PANoptosis and its downstream EMT-fibrosis cascade, offering novel therapeutic targets for CAD intervention.