Exploring PU.1 as a Therapeutic Target to Mitigate Oxidative Stress and Inflammation in Peritoneal Dialysis-Induced Peritoneal Fibrosis.

The transcription factor PU.1 has been implicated in various fibrotic diseases; however, its role in peritoneal dialysis-associated peritoneal fibrosis (PF) remains unclear. The role of PU.1 was investigated using knockdown approaches with AAV9-shPU.1 in a rat PF model and siRNA in human peritoneal mesothelial cells (MeT-5A). Multiple experimental techniques, including real-time quantitative PCR, western blot, enzyme-linked immunosorbent assay (ELISA), and immunohistochemical staining, were utilized. In vivo, PU.1 expression was significantly upregulated in the rat PF model. Knockdown of PU.1 ameliorated peritoneal thickening, collagen deposition, angiogenesis, inflammation, and oxidative stress. In vitro, high-glucose exposure upregulated PU.1 expression in MeT-5A cells, promoting fibrosis and angiogenesis. PU.1 knockdown reduced fibrosis-related markers and suppressed the IL-6/JAK1/STAT3 signaling pathway, a critical regulator of PF. Treatment with an IL-6 inhibitor further confirmed that PU.1 modulates fibrosis through this pathway. PU.1 plays a pivotal role in the progression of PF. Its knockdown mitigates fibrosis by reducing inflammation and angiogenesis, and suppressing the activation of the IL-6/JAK1/STAT3 pathway, highlighting its potential as a therapeutic target.