Marked for destruction? When S-nitrosylation writes protein fate through metabolic rewiring

Metabolism and autophagy are closely interconnected, but whether metabolic alterations can chemically modify proteins and influence their selective autophagic degradation remains poorly understood. Our recent findings show that increased S-nitrosylation resulting from the loss of the denitrosylase AKR1A1/SCoR impairs glycolysis and promotes methylglyoxal accumulation, leading to carbonyl modification and selective autophagic degradation of KEAP1. These findings suggest that metabolic rewiring can influence the fate of specific proteins. In particular, we discuss whether glycation may act as a metabolic "mark" for selective autophagy and how the removal of metabolically modified proteins may, in turn, sustain signaling pathways involved in tumor progression and therapy resistance.