Irisin Restrains Oligodendroglial Ferroptosis to Preserve White Matter After Traumatic Brain Injury via AMPK Activation

ABSTRACT Traumatic brain injury (TBI) results in diffuse white matter (WM) damage, which is a major determinant of death and long‐term disability. Irisin, a myokine with promising neuroprotective effects, but whether irisin modulates WM injury after TBI remains unknown. Using a controlled cortical impact (CCI) mouse model, we evaluated post‐TBI irisin expression and its protective effects on neurological function and WM integrity. Multiple experimental approaches, such as RT‐qPCR, Liperfluo staining, Western blot, and transmission electron microscopy, were employed to assess oligodendrocyte precursor cell (OPC) ferroptosis and relevant signaling pathways. The xCT inhibitor IKE, AMPK inhibitor Compound C, and cFOS siRNAs were employed to explore the underlying mechanisms. TBI transiently suppressed peri‐lesional irisin expression. Irisin treatment improved motor and cognitive performance, attenuated demyelination and the loss of OPCs in peri‐lesional WM. Mechanistically, TBI triggered an xCT‐dependent ferroptotic program, which was counteracted by irisin. Additionally, irisin activated AMPK, thereby suppressing the expression of cFOS, a transcriptional repressor of xCT. Compound C abrogated the protective effects of irisin and cFOS silencing, indicating an AMPK‐dependent irisin–cFOS–xCT/GPX4 axis. TBI suppresses endogenous irisin. Restoration with exogenous irisin protects OPCs against ferroptosis, thereby preserving WM integrity and ultimately improving functional recovery.