Targeting CH25H/25HC-ferroptosis axis: a novel mechanism of MSC-EVs mediated renoprotection in ischemic AKI

作者：Qin Yang, Yu Shrike Zhang, Si-Jie Chen, Jing Song, Qing Yin, Yi Wen, Hong-Bin Yang, Qiuli Wu, Yu Shrike Zhang, Y. Fu, Bo Wang, Min Yang, Suo-Fu Qin, Lin-Li Lv, Tao-Tao Tang, Bi-Cheng Liu · 发表于：Journal of Nanobiotechnology · 年份：2026 · DOI：10.1186/s12951-026-04339-9 · 被引用次数：1 · 研究领域：Ferroptosis and cancer prognosis、Extracellular vesicles in disease、Inflammasome and immune disorders

BACKGROUND: Acute kidney injury (AKI) remains a major clinical challenge due to the lack of effective interventions. While mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show therapeutic promise for AKI, their exact mechanisms are largely to be understood. METHODS: Human umbilical cord-derived MSC-EVs were isolated, characterized, and tested in a murine bilateral renal ischemia reperfusion injury (bIRI) model and in hypoxia/reoxygenation (H/R) treated tubular epithelial cells in vitro. Integrated transcriptomic, miRNA, and biochemical analyses were performed to elucidate the metabolic pathways and molecular mechanisms underlying the renoprotective effects of MSC-EVs. RESULTS: MSC-EVs preferentially targeted injured kidneys and significantly improved renal function, ameliorated tubular injury, and suppressed inflammation in IRI-AKI. RNA sequencing and targeted metabolomics revealed substantial dysregulation of steroid metabolism after IRI, marked by activation of the cholesterol 25-hydroxylase (CH25H)/25-hydroxycholesterol (25HC) axis. Importantly, accumulated 25HC induced lipid peroxidation and ferroptosis in tubular epithelial cells. MSC-EVs treatment reversed these pathological changes by downregulating CH25H, lowering 25HC levels, and restoring redox homeostasis. miRNA profiling further identified miR-26b-5p as a key MSC-EVs cargo that directly targets the 3'UTR of CH25H mRNA to repress its expression. Notably, inhibiting miR-26b-5p within EVs abrogated the...