Lysine malonylation as a therapeutic target: implications for metabolic, inflammatory, and oncological disorders.

Lysine malonylation (Kmal) is an emerging posttranslational modification (PTM) intricately linked to cellular metabolism and disease pathogenesis. This review explores the regulatory mechanisms of Kmal, emphasizing the role of malonyl-CoA as its donor substrate and Sirtuin 5 (SIRT5) as its primary demalonylase. Kmal significantly influences metabolic homeostasis, inflammation, and cancer by modifying key enzymes involved in glycolysis, fatty acid oxidation, and mitochondrial function. In metabolic disorders such as type 2 diabetes and obesity, aberrant malonylation contributes to insulin resistance, lipid accumulation, and oxidative stress. Inflammatory conditions, including sepsis and autoimmune diseases, involve malonylation-driven regulation of immune responses, particularly through GAPDH-mediated cytokine translation. Furthermore, in oncogenesis, malonylation plays a dual role: it suppresses tumor growth by impairing metabolic flux while also being exploited by cancer cells to maintain proliferation. Therapeutic interventions targeting Kmal include SIRT5 modulators, malonyl-CoA metabolism regulators, and small-molecule inhibitors that modulate lysine acylation dynamics. Advances in mass spectrometry and proteomics have expanded our understanding of the biological functions of Kmal; however, its full physiological and pathological significance remains under investigation. Future research should focus on elucidating tissue-specific malonylation patterns and their interactions with other PTMs to refine therapeutic strategies. By integrating metabolic regulation with disease mechanisms, Kmal has emerged as a crucial biochemical modification with broad implications for metabolic, inflammatory, and oncological disorders. Understanding its regulatory network will be pivotal in developing precision medicine approaches aimed at mitigating disease progression and restoring cellular homeostasis.