Protein lipoylation in cancer: metabolic reprogramming and therapeutic potential

Protein lipoylation, a mitochondria-specific post-translational modification (PTM) evolutionarily conserved from bacteria to mammals, plays critical role in metabolic processes. In humans, four identified lipoylated proteins serve as essential components of key enzymes involved in glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism. The dynamic addition or removal of lipoylation modifications critically regulates the functional activity of these enzymes, with dysregulation strongly associated with cancers. Notably, cancer-associated metabolic reprogramming frequently coincides with functional impairment of lipoylated proteins, which subsequently modulates tumor growth through metabolic adaptation. In this review, we systematically summarized the biosynthesis of lipoic acid (LA), introduced the basic structure of lipoylated protein and presented the regulation of lipoylation. Since metabolic reprogramming is an important feature of tumorigenesis, we discussed the relationship between protein lipoylation and tumor metabolic reprogramming. Cuproptosis is a novel form of cell death characterized by copper-mediated lipoylation, which disrupts mitochondrial metabolism and induces cell death through the aggregation of lipoylated proteins in the TCA cycle. We highlighted the therapeutic potential of targeting lipoylation to disrupt cancer cell energy metabolism, particularly through cuproptosis. These insights reveal the intricate interplay between lipoylation and cancer progression and open new avenues for developing targeted therapies. Furthermore, we proposed innovative combinatorial strategies leveraging the crosstalk between cuproptosis and ferroptosis to overcome tumor drug resistance. These insights establish lipoylation as a promising therapeutic axis for developing precision cancer therapies targeting metabolic vulnerabilities.