Fig. 5: Acetylation regulatory mechanism of apoptosis.

A HAAPIR and NAT10 acetylate Tfec mRNA transcripts through ac4C, which promotes the expression of the BIK gene, facilitating apoptosis. B KAT2B can bind to the transcriptional repressor RBPJ while increasing the acetylation level of RBPJ. Acetylated RBPJ binds to the promoter of MCM4, inhibiting the expression of the MCM4 gene, thereby leading to DNA damage and promoting apoptosis. C OC2 can directly bind to the promoter of SKP2 and regulate its expression; downregulation of OC2 also results in decreased SKP2 expression. The downregulation of both releases p300, thereby promoting the acetylation of P53 and further facilitating apoptosis. D When Sirt1 expression significantly decreases, the deacetylation level of FoxO3a is restricted. Hyperacetylated FoxO3a leads to a decrease in BIM expression, promoting apoptosis. E FAO increases CoA, triggering the acetylation of STAT3, and acetylated STAT3 upregulates the expression of ACSL4, which in turn leads to increased phospholipid synthesis and enhances mitochondrial integrity, thereby overcoming cellular apoptosis. In mitochondria, PKM2 is a key metabolic enzyme. When PKM2 accumulates in the mitochondria and undergoes hyperacetylation, it leads to a decrease in Bcl-2 expression. The action of SIRT3 on the K433 residue of PKM2 reduces its acetylation level, thereby stabilizing Bcl-2 expression and exerting an anti-apoptotic effect. Additionally, the MCU with high acetylation levels is in an activated state, resulting in a substantial influx of Ca²⁺ into the mitochondria, which causes mitochondrial Ca²⁺ overload and depolarization, ultimately triggering apoptosis. Acetylation of Cytc at K39 and K53 reduces its binding with Apaf-1, thereby inhibiting apoptosis. Furthermore, when the level of α-tubulin acetylation reaches a certain threshold, cells undergo apoptosis rather than autophagy. HAAPIR heterogeneous nuclear ribonucleoprotein A1-associated protein interacting with RNA, NAT10 N-acetyltransferase 10, ac4C N-acetyltransferase 4C, Tfec transcription factor EC, BIK Bcl-2 interacting killer, KAT2B lysine acetyltransferase 2B, RBPJ recombination signal binding protein for immunoglobulin kappa J region, MCM4 minichromosome maintenance 4, OC2 Onecut2, SKP2 S-phase kinase-associated protein 2, p300 E1A-associated protein p300, Sirt1 sirtuin 1, FoxO3a forkhead box O3, BIM Bcl-2 interacting mediator of cell death, FAO fatty acid oxidation, CoA coenzyme A, STAT3 signal transducer and activator of transcription 3, ACSL4 Acyl-CoA synthetase long-chain family member 4, PKM2 pyruvate kinase M2, Bcl-2 B-cell lymphoma 2, SIRT3 sirtuin 3, MCU mitochondrial calcium uniporter, Cytc cytochrome c, Apaf-1 apoptotic protease-activating factor 1.