The pivotal role of cholesterol metabolism in peripheral nerve regeneration

Peripheral nerve injury (PNI) remains a significant clinical challenge due to the difficulty in achieving complete structural and functional recovery after injury. Recent studies have demonstrated that cholesterol metabolism serves not only as an essential substrate for myelin formation and maintenance, but also exerts critical regulatory roles in axonal regeneration, Schwann cell reprogramming, inflammatory modulation, and remyelination following injury. However, the complex mechanisms linking cholesterol metabolism to peripheral nerve regeneration remain insufficiently elucidated. Existing evidence suggests that injured Schwann cells, macrophages, and neurons can establish a dynamic lipid transport network through apolipoproteins, lipoprotein receptors, and cholesterol-sensing signaling pathways, thereby coordinating metabolic homeostasis and immune responses within the regenerative microenvironment. This review systematically summarizes the dynamic alterations in cholesterol metabolism following peripheral nerve injury and its mechanistic roles in the nerve repair process, with particular emphasis on the regulatory molecules and signaling pathways involved in cholesterol synthesis, transport, uptake, efflux, and neurosteroidogenesis. Furthermore, this review outlines current potential therapeutic strategies targeting cholesterol metabolism, including liver X receptor (LXR) agonists, apolipoprotein E (ApoE)-mimetic peptides, and neurosteroid-related interventions, and analyzes their prospective applications in promoting nerve regeneration and functional recovery. Finally, this review discusses the major challenges and pressing scientific questions facing this field, and presents future perspectives on the construction of cell-type-specific metabolic atlases, the application of multi-omics technologies, and the direction of clinical translational research, providing theoretical foundations and novel research insights for the development of peripheral nerve repair strategies targeting cholesterol metabolism.