Toll-like receptor 4 signaling links cytoskeletal remodeling to lipid accumulation in macrophages.

Macrophage lipid accumulation is a hallmark of atherosclerosis and other metabolic diseases. Toll-like receptor 4 (TLR4) signaling and cytoskeletal remodeling have each been implicated in this process, yet the mechanistic connections among these three elements remain incompletely defined. This review synthesizes current evidence for pathways in which TLR4 activation, via bifurcated signaling through MyD88/TRAM, SYK/Src, and integrins, engages small GTPases (Rac, Cdc42, Rho) and downstream effectors including cofilin and paxillin to drive cytoskeletal remodeling. These cytoskeletal changes facilitate lipid internalization through multiple routes, including macropinocytosis, receptor redistribution, and lysosomal synapse formation, and regulate lipid droplet dynamics, ultimately promoting foam cell formation. We also discuss the therapeutic potential and safety challenges of targeting cytoskeletal regulators in diseases such as atherosclerosis. The convergence of TLR4 signaling, cytoskeletal remodeling, and lipid metabolism represents a compelling mechanistic nexus for understanding foam cell formation. Elucidating the molecular details of this pathway-particularly the SYK/Src-cytoskeleton axis-may reveal macrophage-selective therapeutic targets that suppress pathological lipid accumulation while preserving host defense functions.