Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Attenuate Renal Fibrosis by Suppressing Fibroblast Activation via the INHBA/PI3K/AKT Pathway.

Renal fibrosis is a common pathological feature and key driver of progression to end-stage renal disease in various chronic kidney diseases, with effective treatments remaining scarce. Exosomes derived from mesenchymal stem cells (MSC-Exos) have demonstrated tremendous potential in tissue and organ repair and antifibrosis treatment. This study investigated the therapeutic effects and mechanisms of MSC-Exo derived from human umbilical cord (HucMSC-Exo) on renal fibrosis. HucMSC-Exo was applied to intervene in a mouse model of renal fibrosis induced by unilateral ureteral obstruction (UUO) or cocultured with TGF-β-stimulated rat renal fibroblasts (NRK-49F). Results showed that HucMSC-Exo conspicuously alleviated pathological damage, inflammatory response, fibroblast proliferation/activation, and extracellular matrix deposition in UUO kidneys. Single-cell sequencing revealed a prominent upregulation of Inhba gene in UUO kidneys, whereas HucMSC-Exo treatment effectively inhibited its expression. Further mechanistic studies showed that knocking down Inhba mimicked the antifibrotic effects of HucMSC-Exo, whereas exogenously adding INHBA weakened its protective effects. Transcriptome sequencing results revealed that the downstream effects of Inhba involve regulating the PI3K/AKT signaling pathway, and HucMSC-Exo treatment markedly inhibited the activation of this pathway. Collectively, HucMSC‑Exo exerts antifibrotic effects by regulating the INHBA/PI3K/AKT signaling axis to inhibit renal fibroblast activation.