Regulation of inflammation by oxidized lipids

Host-derived lipids undergoing enzymatic or nonenzymatic oxidation play critical roles in regulating inflammation. Polyunsaturated fatty acids, cholesterol, and cholesterol intermediates can be enzymatically oxidized and serve as signaling mediators controlling tissue homeostasis and immunity. Spontaneously generated oxidized lipids, including nonenzymatically oxidized phospholipids (oxPLs), result from oxidative stress and accumulate during inflammation, affecting cellular metabolism, immune cell functions, and cell fate. These distinct classes of oxidized lipids not only share overlapping inflammatory roles but also exhibit divergent effects depending on their molecular structures and cellular targets. This Review highlights the double-edged nature of oxPLs: Although their transient production triggers protective responses, their accumulation sustains inflammation, contributing to tissue damage. We also discuss the emerging roles of oxPLs in cell death programs, immune cell activation, and stromal cell functions, which are critical processes favoring tumor growth. Overall, we highlight how oxidized lipids orchestrate immune responses and explore their contribution to infectious diseases and cancer.