Rescuing Prdx1-deficiency-mediated redox homeostasis disruption in bone marrow mesenchymal stem cells ameliorate radiation-induced bone loss.

Ionizing radiation (IR) is a major cause of accelerated skeletal aging and severe bone loss, primarily by triggering oxidative stress and promoting premature senescence(definition) in bone marrow mesenchymal stem cells (BMSCs). This mechanism underscores a critical need for redox-based intervention. Peroxiredoxin 1 (Prdx1), a vital thiol peroxidase and redox sensor, is recognized for its potent anti-oxidative and anti-senescence capabilities. However, the precise function and underlying mechanism of Prdx1 in protecting BMSCs from IR-induced bone loss remain unexplored. Through Single-cell RNA-sequencing (scRNA-seq) and IR-induced bone loss mice model, we found that the Prdx1 expression in BMSCs exhibited a transient elevation in early stage after IR, while its expression was downregulated in late stage after IR. A prdx1-knockout mice (Prdx1^KO) was constructed and exhibited aggravated bone loss after IR. Prdx1^KO-derived primary BMSCs exhibited elevated oxidative stress and cellular senescence level, confirming a protective role for Prdx1. By high-throughput RNA-sequencing (RNA-seq), transcriptional factor prediction, molecular dynamic simulation, we verified that Prdx1 inhibited BMSCs oxidative stress injury via interacting with Pten and suppressing the Akt/FoxO signaling pathway. A BMSCs-specific E7 affinity peptide modified extracellular vesicle (EV) delivery system E7-EV^Prdx1 was constructed to achieve targeted delivery of Prdx1 mRNA to BMSCs. E7-EV^Prdx1 effectively suppressed IR-induced oxidative stress injury in vitro. Systemic administration of E7-EV^Prdx1 effectively rescued IR-induced bone loss and demonstrated favourable biocompatibility in vivo. Our study identifies Prdx1 as a pivotal redox-regulated target in IR-induced BMSCs injury and introduces E7-EV^Prdx1 as a novel, highly efficient, and safe gene therapy strategy for mitigating IR-induced bone loss.