PPARa-FSP1 axis modulates lipid peroxidation-induced neuronal ferroptosis to promote functional recovery in mouse model of traumatic spinal cord injury.

Prior studies have shown that inhibiting ferroptosis could facilitate neural repair following traumatic spinal cord injury (TSCI), yet the underlying mechanisms remain unclear. In this study, we first demonstrated that ferroptosis occurred locally at the injury site of TSCI, and was closely associated with lipid metabolism and the PPARa signaling pathway. Notably, we observed a significant decrease in PPARa expression in neurons during the early stage of TSCI, and modulating PPARa activity influences lipid peroxidation-induced ferroptosis, which was linked to preservation of motor function. Mechanistically, we identified PPARa as a transcriptional activator of FSP1, which subsequently activated the CoQ10-NAD(P)H antioxidant system to inhibit ferroptosis through a GPX4-independent pathway. Furthermore, we found that the distribution of FSP1 in the spinal cord mirrored that of PPARa, with high expression in neurons and a notable decline during the early stages of TSCI. Finally, we confirmed that the PPARa-FSP1 pathway modulated neuronal responses to lipid peroxidation-induced ferroptosis following TSCI, promoting functional recovery. In conclusion, our findings highlighted that PPARa promoted TSCI recovery by suppressing lipid peroxidation-induced neuronal ferroptosis via the FSP1 pathway, and positioned the PPARa-FSP1 axis as a central mechanism in post-TSCI ferroptosis and a promising therapeutic target. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-026-06082-8.