Metabolite-driven protein post-translational modifications: network mechanisms bridging metabolic sensing and functional regulation

Metabolites have traditionally been viewed primarily as energy sources and biosynthetic substrates for cells. However, the discovery of novel protein modifications such as lactylation, succinylation, and O-GlcNAcylation demonstrates that metabolites can also function as signaling molecules, whose activated high-energy derivatives directly drive post-translational modifications (PTMs) of proteins. The regulatory axis of ‘metabolic sensing–PTM remodeling–cellular functional reprogramming’ that emerges from this plays a significant role in the pathogenesis of tumors, immune disorders, and metabolic genetic diseases. This review centers on this regulatory axis. We first elaborate the chemical-structural basis governing metabolite-driven PTM biogenesis, followed by discussion of upstream metabolic-pathway activation and downstream regulatory outputs, including chromatin remodeling, protein phase separation and metabolic feedback circuits. Based on this, we employ cross-species comparisons to discuss the evolutionary conservation and functional divergence of this axis. This analysis clarifies several long-standing controversies, including the distinction between enzymatic and non-enzymatic modifications, the crosstalk between different modifications, the concentration thresholds required in vivo and in vitro for modification occurrence, and the strategies for validating causality. Finally, advances in technologies such as single-cell and spatial multi-omics, live-cell metabolic probes, targeted small-molecule tools, and systems modeling are discussed to explore their potential applications, aiming to provide insights for biomarker discovery and precision intervention in metabolic diseases. Central to this review is the emphasis on chemical and biophysical constraints governing metabolite-driven PTMs, which shape their occurrence, compartment-dependent enzyme-dependence, and downstream biological outputs.