Fatty acid metabolism and lipid channeling in macrophages: mechanisms of inflammation, resolution, and lipotoxicity

Macrophages integrate metabolic signals with immune activation, and their ability to handle fatty acids is central to preventing lipotoxicity and to sustaining effector functions. In cardiometabolic settings such as obesity, metabolic dysfunction-associated steatotic liver disease, and atherosclerosis, chronic exposure to excess free fatty acids and toxic lipid species, such as ceramides, disrupts organelle integrity, impairs efferocytosis, and skews macrophages toward pro-inflammatory phenotypes. This review examines how macrophages channel fatty acids into β-oxidation, glycerolipid synthesis and storage, sphingolipid production, and polyunsaturated fatty acid-derived lipid mediator biosynthesis to shape the balance among metabolic adaptation, inflammatory activation, resolution, and lipid-induced dysfunction. We also highlight lipin-1 as a regulatory node at a key branchpoint in macrophage lipid metabolism. By linking glycerolipid synthesis, lipid storage, mitochondrial metabolism, and inflammatory signaling, lipin-1 illustrates how lipid routing can influence macrophage function in cardiometabolic disease.