〔Abstract〕 Abstract Objective To clarify the intrinsic link between a high-fat diet (HFD) and the pathological progression and prognosis of spinal cord injury (SCI) while preliminarily exploring the potential underlying mechanisms . Meth- ods SCI models were established in mice that were fed either a regular diet (RD) or HFD , with injury inflicted specifically on the T9 - T12 segments . Hematoxylin-Eosin (HE) staining , Masson staining , and Nissl staining were used to observe the local histological changes in SCI tissues . The Basso , Beattie , and Bresnahan (BBB) score and footprint analysis were used to evaluate and compare hindlimb functional recovery after SCI in both RD and HFD mice . In vitro experiments were conducted to identify key fatty acids in the HFD that exacerbate neuronal damage , while in vivo experiments assessed the effects of 2-bromopalmitate (2-BP) , a palmitic acid inhibitor , on HFD-fed mice with SCI . Results Compared to RD-fed mice , HFD-fed mice exhibited significantly larger lesion areas , more severe neuronal damage , and poorer hindlimb functional recovery after SCI . Palmitic acid was identified as the key fatty acid aggravating neuronal damage . Further more , inhibition of palmitoylation , mediated by palmitic acid , en- hanced neuronal survival , promoted tissue repair , and improved hindlimb functional recovery in HFD-fed mice post-SCI . Conclusion HFD exacerbates pathological damage following SCI in mice through palmitic acid , impai- ring recovery. Palmitic acid-mediated palmitoylation is likely the main mechanism underlying this effect.