Mesenchymal stem cell-derived exosomes alleviate renal interstitial fibrosis via pVHL-mediated HIF-1α ubiquitination and degradation

Chronic kidney disease (CKD) is a global health burden that frequently progresses to renal interstitial fibrosis. Mesenchymal stem cell–derived exosomes (MSC-Ex) have shown therapeutic potential in kidney repair, yet their role in hypoxia-driven fibrosis remains undefined. We tested whether human umbilical cord MSC exosomes (hucMSC-Ex) attenuate fibrosis by delivering von Hippel-Lindau tumor suppressor protein (pVHL) to destabilize hypoxia-inducible factor-1α (HIF-1α). Hypoxia combined with mechanical stress increased nuclear HIF-1α levels in UUO tubules and triggered fibrosis. HucMSC-Ex markedly reduced renal collagen and α-SMA. Mechanistically, hucMSC-Ex were enriched in pVHL and increased pVHL abundance in recipient renal cells, promoting HIF-1α ubiquitination and proteasome-dependent degradation. HucMSC-Ex alleviate renal interstitial fibrosis by delivering pVHL to facilitate HIF-1α ubiquitination and degradation, thereby providing a cell-free anti-fibrotic strategy.