Short Overview on the Involvement of Lipid Peroxidation Product 4-Hydroxynonenal in Diverse Pathways of Cell Death

The oxidation of lipids, notably of polyunsaturated fatty acids (PUFAs), under oxidative stress is a self-catalyzed chain reaction that generates reactive aldehydes, among which 4-hydroxynonenal (4-HNE) is considered to act as a second messenger of free radicals. The pleiotropic effects of 4-HNE, which include the regulation of cellular antioxidant capacities, proliferation, differentiation, and apoptosis, are concentration-dependent as they depend on cell type. Therefore, 4-HNE has important roles in various pathophysiological processes and the pathogenesis of acute and chronic diseases, especially degenerative and malignant diseases. Before 4-HNE was recognized as a signaling molecule, it was known to be the cytotoxic mediator of oxidative stress, acting even if lipid peroxidation was not present, because it remains bound to proteins, changing their structure and function. Research in this field has revealed several novel modes of activities of 4-HNE associated with cell death, including not only apoptosis/programmed cell death and necrosis but also ferroptosis, autophagy, pyroptosis, necroptosis, parthanatos, oxeiptosis and cuproptosis. This review shortly summarizes these findings, aiming to encourage further research in the field that might open new ways to use 4-HNE as the bioactive factor for targeted cell death, in particular cancer cells.