Targeting the Nrf2/TGF‐β1/Smad Signaling Pathway: A Novel Strategy for Urolithin A to Alleviate Renal Fibrosis

ABSTRACT The global prevalence and mortality rates associated with chronic kidney disease (CKD) have been on a continuous rise over recent decades. Renal fibrosis (RF) serves as a critical factor in the progression of CKD to end‐stage renal disease. This study aims to investigate the effect of urolithin A (UroA) on folic acid‐induced RF and to elucidate its underlying mechanisms. By establishing a mouse model of renal fibrosis and an in vitro model of epithelial‐mesenchymal transition (EMT) using human renal proximal tubule epithelial cells (HK‐2), the findings indicate that UroA has the potential to enhance renal function, mitigate renal pathological damage, and inhibit the expression of extracellular matrix components as well as the EMT process in mice with RF. Mechanistically, UroA promotes the phosphorylation of Nrf2 and its subsequent nuclear translocation, thereby activating the Nrf2/HO‐1 signaling pathway to counteract oxidative stress. Furthermore, UroA modulates the Smad signaling pathway by upregulating Nrf2, which in turn reduces the EMT of HK‐2 cells induced by TGF‐β1. These results suggest that orally administered UroA represents a promising therapeutic strategy capable of ameliorating cellular oxidative damage, obstructing EMT, reducing renal injury, and delaying the decline in renal function by regulating the Nrf2/TGF‐β1/Smad axis. This distinctive mechanism offers valuable insights into targeted therapeutic strategies for RF and the potential application of UroA.