Fig. 4

Mechanisms linking novel HPTMs to cancer development through metabolic pathways. The p300 protein possesses key lysine 2-hydroxyisobutyryltransferase activity, playing a crucial role in regulating glycolysis. Aspirin, by specifically hydroxyisobutyrylating at certain sites, inhibits the 2-hydroxyisobutyrylation of the key glycolytic enzyme ENO1, thereby reducing its activity and consequently inhibiting the growth of tumor cells. Additionally, the rate of aerobic glycolysis in tumor cells is increased, accompanied by an increase in histone lactylation, which transcriptionally supports the expression of c-Myc. As a critical transcription factor, c-Myc further upregulates the expression of SRSF10, promoting the selective splicing of MDM4 and Bcl-x in breast cancer cells, thus affecting the growth and survival of cancer cells. On the other hand, aspirin significantly reduces the succ levels of PGAM1 in liver cancer cells, thereby inhibiting glycolysis. Concurrently, 2-hydroxybutyrate induces 2-hydroxyisobutyrylation modifications of p53 at lysine residues 120, 319, and 370. These modifications lead to reduced acetylation levels of p53, subsequently downregulating the expression of downstream genes p21 and PUMA, ultimately resulting in reduced growth and apoptosis of cancer cells