The 4-Hydroxynonenal-Protein Adducts and Their Biological Relevance: Are Some Proteins Preferred Targets?

It is well known that oxidative stress and lipid peroxidation (LPO) play a role in physiology and pathology. The most studied LPO product with pleiotropic capabilities is 4-hydroxynonenal (4-HNE). It is considered as an important mediator of cellular signaling processes and a second messenger of reactive oxygen species. The effects of 4-HNE are mainly attributed to its adduction with proteins. Whereas the Michael adducts thus formed are preferred in an order of potency of cysteine > histidine > lysine over Schiff base formation, it is not known which proteins are the preferred targets for 4-HNE under what physiological or pathological conditions. In this review, we briefly discuss the methods used to identify 4-HNE-protein adducts, the progress of mass spectrometry in deciphering the specific protein targets, and their biological relevance, focusing on the role of 4-HNE protein adducts in the adaptive response through modulation of the NRF2/KEAP1 pathway and ferroptosis.

Automated summary

It is well known that oxidative stress and lipid peroxidation have significant effects on physiology and pathology. Among the lipid peroxidation products, 4-hydroxynonenal (4-HNE) is the most extensively studied. It acts as an important mediator of cellular signaling and a second messenger of reactive oxygen species. However, the specific protein targets and their biological relevance in the presence of 4-HNE are not fully understood. This review summarizes the methods used to identify 4-HNE-protein adducts, the progress in mass spectrometry for deciphering the specific protein targets, and their role in the adaptive response through the NRF2/KEAP1 pathway and ferroptosis.