Lipid Signaling and Foam Cell Formation in Atherosclerosis and Spinal Cord Injury

Macrophages and microglia serve as both "scavengers" and "immune sentinels" to maintain tissue homeostasis. However, when the lipid load exceeds their processing capacity, these cells transform into foam cells, thereby driving chronic inflammation and impairing tissue repair. Despite their distinct organ systems, atherosclerosis (AS) and spinal cord injury (SCI) converge on a common pathological cascade-foam cell formation-characterized by "enhanced lipid uptake, impaired cholesterol efflux, disrupted lysosomal/autophagic processing, and ER stress/ROS/NLRP3-mediated inflammatory amplification." This review systematically dissects and compares the molecular mechanisms underlying macrophage foaming in AS and SCI, with a particular focus on the similarities and differences in ABCA1/ABCG1-mediated cholesterol efflux, lipid droplet autophagy, the ER stress-NLRP3 axis, and nuclear receptor regulatory networks. Furthermore, it explores therapeutic avenues that target lipid metabolic reprogramming, including natural products, biomimetic nanomedicines, and genetic interventions. By establishing a cross-disease framework for lipid homeostasis disruption, this paper challenges traditional organ-centric views and provides a theoretical foundation that may accelerate the development of shared therapeutic strategies for AS and SCI.