Fig. 6: Mechanism of acetylation regulation of ferroptosis.

A Acetylated P53 is not easily degraded and downregulates the expression of SLC7A11, inhibiting ferroptosis; Irisin and resveratrol entering the cell can elevate the level of Sirt1, leading to the deacetylation of P53. Additionally, Sirt3, HDAC4, and HDAC5 in the cytoplasm can also deacetylate P53, upregulating SLC7A11 and inhibiting ferroptosis. FXR and STAT6 undergo competitive inhibition with CBP, reducing the acetylation of p53, thereby upregulating the expression of SLC7A11 and inhibiting ferroptosis. B CAP enhances the acetylation modification level of HOXB9 by promoting the interaction between HOXB9 and PCAF; acetylated HOXB9 elevates its ubiquitination modification level and leads to its degradation, decreasing HOXB9’s ability to regulate LC7A11 expression as a transcription factor, promoting ferroptosis. C LPCAT2 regulates the acetylation of PRMT1 at the K145 site, preventing the cytoplasmic transport of PRMT1 within the cell, resulting in a loss of PRMT1-mediated asymmetric dimethylation of arginine 3 on the H4 histone of LC7A11, limiting transcriptional activation of LC7A11 and promoting ferroptosis. The acetylation of the H3 lysine 27 site of LC7A11 serves as a marker that recruits GAS41; GAS41 activates the expression of LC7A11 by bridging NRF2 with the H3K27ac site, inhibiting ferroptosis. NAT10 suppresses ferroptosis by stabilizing SLC7A11 mRNA through acetylation. D HMGCL modulates H3K9 acetylation via β-OHB and dose-dependently regulates the expression of DPP4, which inhibits SLC7A11 expression to control ferroptosis. E HMGA2 is an important transcription factor that binds to and promotes cis-element modifications in the GPX4 gene promoter region, enhancing enhancer activity by increasing H3K4 methylation and H3K27 acetylation. F NAT10 inhibits ferroptosis by stabilizing FSP1 mRNA transcripts through ac4C RNA modification. G FEACR binds to NAMPT, stabilizing the latter; NAMPT increases NAD⁺ synthesis, promoting Sirt1 expression, which in turn reduces FOXO1 acetylation levels. The latter upregulates the transcription of FTH1, inhibiting ferroptosis. H KAT6B induces acetylation of H3 lysine 23 in cells and enriches RNA pol II at the STAT3 promoter; STAT3 can bind to consensus DNA response elements in the promoters of GPX4, SLC7A11, and FTH1, regulating ferroptosis. I The HPV oncogenes E6 and E7 upregulate TUBORF on one hand through p300-mediated acetylation of histone H3 lysine 27; on the other hand, they recruit ESCO1 to bind and acetylate TUBORF, which subsequently leads to the degradation of IRGQ via the ubiquitin–proteasome pathway. The inhibition of IRGQ upregulates the expression of SLC7A11 and GPX4 proteins, ultimately enhancing resistance to ferroptosis. In the endoplasmic reticulum, the EP300 acetyltransferase promotes ferroptosis by acetylating the K353 site of HSPA5, while HDAC6 limits the acetylation of HSPA5 and the subsequent ferroptosis. The mechanism involves HSPA5 mediating resistance to ferroptosis by maintaining the stability of the GPX4 protein. SIRT3 also directly participates in the acetylation modification of GPX4. When SIRT3 expression decreases, GPX4 becomes highly acetylated, leading to a reduction in GPX4 protein levels and promoting ferroptosis. In mitochondria, SLC25A1 drives the transport of citrate from the mitochondria to the cytoplasm and provides energy for ACLY to synthesize acetyl-CoA. This, together with KAT2B, maintains the acetylation of FSP1, preventing its ubiquitination and subsequent degradation, while HDAC3 reverses this process. The reduction of mitochondrial SIRT3 leads to an increase in the acetylation level of DHODH; high acetylation levels of DHODH hinder pyrimidine biosynthesis and the production of CoQH2, thereby promoting ferroptosis. TIGAR translocates to the mitochondria, enhancing the interaction between SIRT5 and SDH A while reducing the interaction between SIRT3 and SDH A, facilitating the acetylation and deacylation of SDH A, which inhibits SDH activity, subsequently decreasing ROS production and suppressing ferroptosis. Furthermore, NaHS can alleviate the acetylation of ALOX12 and protect membrane lipids from peroxidation, thereby inhibiting ferroptosis. SLC7A11 solute carrier family 7 member 11, Sirt1 sirtuin 1, Sirt3 sirtuin 3, HDAC4 histone deacetylase 4, HDAC5 histone deacetylase 5, FXR farnesoid X receptor, STAT6 signal transducer and activator of transcription 6, CBP CREB-binding protein, CAP cold atmospheric plasma, HOXB9 homeobox B9, PCAF P300/CBP-associated factor, LPCAT2 lysophosphatidylcholine acyltransferase 2, PRMT1 protein arginine methyltransferase 1, GAS41 Gastric cancer associated protein 41, NRF2 nuclear factor erythroid 2-related factor 2, NAT10 N-acetyltransferase 10, HMGCL hydroxymethylglutaryl-CoA lyase, β-OHB beta-hydroxybutyrate, DPP4 dipeptidyl peptidase-4, HMGA2 high mobility group AT-hook 2, GPX4 glutathione peroxidase 4, FSP1 ferroptosis suppressor protein 1, FEACR ferroptosis-related Acyl-CoA binding protein, NAMPT nicotinamide phosphoribosyltransferase, FOXO1 forkhead box O1, FTH1 ferritin heavy chain 1, KAT6B lysine acetyltransferase 6B, STAT3 signal transducer and activator of transcription 3, p300 E1A-binding protein p300, TUBORF tubulin oligomerization factor, ESCO1 establishment of sister chromatid cohesion 1, IRGQ immunity-related GTPase Q, EP300 E1A-binding protein p300, HSPA5 heat shock protein family A member 5, HDAC6 histone deacetylase 6, SLC25A1 solute carrier family 25 member 1, ACLY ATP citrate lyase, KAT2B lysine acetyltransferase 2B, HDAC3 histone deacetylase 3, DHODH dihydroorotate dehydrogenase, CoQH2 coenzyme Q hydroquinone, TIGAR TP53-inducible glycolysis and apoptosis regulator, SIRT5 sirtuin 5, SDHA succinate dehydrogenase A, ALOX12 arachidonate 12-lipoxygenase.