Transcriptomic analysis reveals that neural stem cell-derived exosomes regulate the HMGB1/TLR2 signaling axis to promote astrocytic differentiation and mitochondrial biogenesis in the repair of radiation-induced blood-brain barrier damage

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Radiation-induced brain injury (RBI) is frequently associated with blood, brain barrier (BBB) disruption, which contributes to poor prognosis. Neural stem cell-derived exosomes (NSC-Exo) have recently attracted attention as mediators of intercellular communication with potential roles in tissue repair. However, how NSC-Exo promote BBB recovery after RBI remains unclear. This study explored whether NSC-Exo restore BBB function by regulating the HMGB1/TLR signaling pathway, thereby promoting endogenous NSC differentiation toward astrocytes and enhancing mitochondrial biogenesis. A rat RBI model was established and treated with NSC-Exo. Molecular marker analysis, transcriptomic profiling, and BBB functional assessment were performed to clarify the underlying mechanisms. The results showed that NSC-Exo enhanced NSC stemness and astrocytic differentiation, improved mitochondrial function, and reduced ROS accumulation. NSC-Exo also suppressed HMGB1/TLR2 pathway activation and promoted BBB repair. Functional experiments further indicated that HMGB1 overexpression weakened the protective effects of NSC-Exo, whereas TLR2 knockdown reversed this effect. In conclusion, NSC-Exo facilitate endogenous NSC remodeling and BBB restoration after RBI, at least partly through regulation of the HMGB1/TLR2 axis, providing a potential strategy for RBI treatment.

Schematic illustration of the molecular mechanism by which NSC-Exo ameliorates RBI through inhibition of the HMGB1/TLR2 signaling pathway.

This study was supported by the Guangzhou Education Bureau (No. 2024312154).

These authors contributed equally: Fanrui Zeng, Yalei Zhang, Yun Zhou.

Department of Radiation Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

Jiangxi University of Traditional Chinese Medicine, Nanchang, China

Department of Medical Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

All experimental procedures were approved by the Animal Ethics Committee of Guangzhou Medical University, and ethical guidelines for animal experiments were strictly followed (Ethics Approval Number: 20240566).

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Zeng, F., Zhang, Y., Zhou, Y. et al. Transcriptomic analysis reveals that neural stem cell-derived exosomes regulate the HMGB1/TLR2 signaling axis to promote astrocytic differentiation and mitochondrial biogenesis in the repair of radiation-induced blood-brain barrier damage. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03250-4

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