Abstract
This study aimed to clarify the role of tyrosine phosphatase SHP-1 on renal fibrosis and its underlying mechanisms. We used a unilateral ureteral obstruction (UUO) rat model to simulate renal fibrosis and achieved overexpression of SHP-1 through lentivirus injection. The effects of overexpression of SHP-1 on extracellular matrix (ECM) deposition, fibrosis degree and key indicators of glycolysis in renal tissue were evaluated. Results showed that overexpression of SHP-1 significantly alleviated renal fibrosis and ECM accumulation induced by UUO. SHP-1 overexpression reduced α-SMA, FN, collagen I, III, HK, PKM2, Bax expression, and lactate levels, while increasing glucose uptake and Bcl-2 expression. Bioinformatics analysis has shown that the transcription factors FOXO (FoxO3a and FoxO1) are downstream targets of the STAT3 signaling pathway, jointly regulating the glycolysis/gluconeogenesis pathway. Overexpression of SHP-1 effectively inhibited the phosphorylation of STAT3 (p-STAT3) and the expression of downstream FoxO3a/FoxO1. Mechanism studies have shown that overexpression of SHP-1 inhibits the STAT3 signaling pathway, generating effects similar to those of glycolytic inhibitors: inhibiting glycolysis, promoting cell proliferation, reducing cell apoptosis and collagen deposition, thereby alleviating renal fibrosis. In conclusion, overexpression of SHP-1 can effectively alleviate the progression of renal fibrosis by inhibiting the STAT3/FOXO signaling axis and its mediated glycolytic reprogramming. This provides new experimental evidence for the development of anti-fibrotic therapies targeting SHP-1.