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

ABSTRACT 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.