Carbonylation-driven oligomerization causes protein discoloration as a potential mechanism of skin tone alteration

Skin yellowness is a predominant age-related concern, particularly among North Asian populations, and is suspected to be associated protein carbonylation. However, the precise chemical mechanisms linking skin yellowness and protein carbonylation remain unclear. This study elucidates these mechanisms by investigating the protein yellowing process induced by carbonylation. Employing both in vitro skin models and a protein solution, this study demonstrates that 4-hydroxynonenal (4-HNE), a representative reactive aldehyde generated by lipid peroxidation, triggers protein carbonylation, which subsequently leads to the formation of cross-linked oligomers that visually manifest as yellowness. Characterization via GB1 model protein and its mutants, NMR and MALDI-TOF mass spectrometry reveals that cross-linked oligomers, rather than the initial carbonylation events, are the primary source of protein discoloration. Furthermore, yellow intensity correlates with the size and/or structure of the oligomers. Finally, nucleophilic scavengers such as glutathione (GSH), cysteine (Cys), and histidine (His) are shown to significantly suppress both protein yellowing and oligomerization. These results establish the first mechanistic connection between protein carbonylation and visible discoloration, offering novel insights for targeted dermatological interventions and advancing the understanding of aging biology and protein chemistry.