The AMPK-BECN1-System Xc⁻ Pathway in Traumatic Brain Injury: Implications for Exosome-Based Therapy.

Secondary neuronal death following traumatic brain injury (TBI) constitutes a central pathological mechanism driving permanent functional deficits. Mounting evidence reveals the “autophagy-ferroptosis axis,” forged by dysfunctional autophagy converging with activated ferroptosis, as a critical driver of this process. This review synthesizes current evidence on the molecular underpinnings of this axis within TBI, suggesting the AMPK (AMP-activated protein kinase)-BECN1 (beclin 1)-System Xc⁻ pathway as one potential core regulatory network. We provide an in-depth exploration of how this network may orchestrate neuronal fate through the “upstream decision-making” of the energy sensor AMPK, the “dual-function bridge” role of BECN1, and the “terminal executioner” function of System Xc⁻. Building upon this foundation, the review further advances an intervention hypothesis leveraging exosomes derived from olfactory ensheathing cells overexpressing brain-derived neurotrophic factor (BDNF-OE-OEC-Exos). We suggest their potential for TBI therapy, while acknowledging that this concept remains to be validated in relevant disease models and human studies.