Integrative multi-omics analysis reveals molecular landscape associated with chronic lipid accumulation following contusive spinal cord injury

Lipid metabolism is a critical process that occurs in the lipid-rich spinal cord during damage and repair. Here, we integrated ultrastructural characteristics with multi-omics analysis as well as transcriptomic, untargeted, targeted proteomic, lipidomic, and N6-methyladenosine (m 6 A) epitranscriptomic profiling in a clinically relevant spinal cord injury (SCI) model. We observed lipid accumulation, lysosome-based autophagy of lipid droplets, and remyelination in the lesion of the chronic phase. The analysis also revealed molecular alterations associated with the enhancement of glycolysis, tricarboxylic acid cycle, and fatty acid metabolism, marked increases in triglyceride species with C16:0 fatty acyl chains, and adaptive changes in cholesterol metabolism. These changes included decreased uptake of cholesterol through Mylip upregulation, decreased synthesis through downregulation of Fdps and Hmgcs1 , and increased efflux through Apoe upregulation. Among these, Mylip and Hmgcs1 are regulated by m 6 A methylation. Altogether, our findings revealed endogenous mechanisms in response to microenvironment changes, highlighting the potential of exploring lipid regulators for SCI treatment.