Chronic kidney disease (CKD) is a major global health problem characterized by renal fibrosis, for which effective therapeutic options are still lacking. Mesenchymal stem cells (MSCs) have emerged as potential candidates for treating fibrosis due to their paracrine effects. This study first compared the antifibrotic capacities of umbilical cord-derived MSCs (UCMSCs) and dental pulp stem cells (DPSCs). The results showed that DPSCs exhibited superior effects in suppressing fibrosis markers and improving the fibrotic microenvironment. Thus, subsequent studies focused on DPSC and their hepatocyte growth factor (HGF)-modified counterpart (HGF-DPSC). Using an in vivo unilateral ureteral obstruction (UUO) mouse model and an in vitro Transforming Growth Factor-Beta 1(TGF-β1)-induced Human Renal Proximal Tubule Epithelial Cell (HK-2 cell) model, this study systematically evaluated the promising antifibrotic effects and mechanisms of DPSC. The results demonstrated that HGF-DPSC significantly improved the fibrotic microenvironment by regulating the Phosphoinositide 3-Kinase/Protein Kinase B/Glycogen Synthase Kinase 3 Beta (PI3K/AKT/GSK3β) signaling pathway and suppressing β-catenin activation. We confirmed direct protein–protein interaction between HGF and Iodothyronine Deiodinase 2 (DIO2) through co-immunoprecipitation (Co-IP), which suggested a novel molecular mechanism by which HGF-DPSC exerts its antifibrotic effects. These findings highlight the multitarget mechanism of HGF-DPSC in the treatment of renal fibrosis and provide new insights and possibilities for the treatment of CKD.
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