Fig. 7: Schematic of acetylation regulation in regulated pyroptosis.

A HDAC2 suppresses the expression of SMAD7 by catalyzing the deacetylation of H3K27 at the SMAD7 promoter; meanwhile, miR-30e-3p promotes the expression of SMAD7 by inhibiting HDAC2 expression through binding with HDAC2 mRNA, thus inhibiting TGF-β-mediated NF-κB activation and exerting an anti-necrotic effect. B ERG concurrently inhibits TNF-α-dependent activation of the ICAM-1 promoter and NF-κB activity; however, HDAC11 may activate NF-κB and promote pyroptosis by regulating the acetylation level of ERG. C p65 typically forms a heterodimer with p50 and remains in the cytoplasm by binding to the inhibitor protein IκB. When cells are stimulated (such as by inflammatory factors or pathogens), IκB is degraded, and p65/p50 translocates to the nucleus, inducing multiple target genes, including those acting on the NLRP3 promoter region. Acetylation of p65 can inhibit the expression of NLRP3, while HDAC6 decreases the acetylation level of p65, promoting pyroptosis; phosphorylated STAT3 recruits EP300 to form a complex that enhances acetylation of histones H3 and H4 at the NLRP3 promoter, leading to cellular pyroptosis, which can be inhibited by colchicine; in addition, P300 directly increases histone acetylation levels at the NLRP3 promoter region, resulting in high expression of NLRP3 and subsequent pyroptosis; overexpression of HDAC2 suppresses the recruitment of the BRD4-p-p65 complex mediated by H3K27ac, thus inhibiting NLRP3 transcription and the occurrence of pyroptosis. D KAT5 promotes STUB1 transcription through acetylation, leading to the ubiquitination and degradation of LATS2 and activation of the YAP/β-catenin pathway. The interaction of YAP and β-catenin in the nucleus can inactive NLRP3 and inhibit pyroptosis; lactate can promote histone H3K9 acetylation and H3K18 lactylation, inhibiting NLRP3 expression and consequently preventing pyroptosis. E The reduction in NAT10 expression leads to a decrease in ULK1 transcripts, thereby reducing ULK1 levels. As a regulator of STING phosphorylation, the absence of ULK1 enhances the activation of the STING-IRF3 signaling pathway, resulting in the nuclear translocation of IRF3 and increased expression of NLRP3. F BRD4 is upregulated during hepatocyte lipotoxicity, subsequently regulating H3K27 acetylation in the GSDMD gene promoter region, thereby enhancing GSDMD expression. G Increased expression of HDAC3 results in decreased H3K27 acetylation of ATG5, which inhibits the expression of ATG5. The HDAC3 inhibitor BRD3308 can upregulate ATG5 expression through a deacetylation effect, which reduces cellular reactive oxygen species accumulation and inhibits pyroptosis. H Elevated levels of BRD4 further regulate H3K27 acetylation in the VDAC gene promoter region, thereby enhancing VDAC expression and recruiting NLRP3 to promote pyroptosis. I Nrf2 can recruit EP300, thereby improving H3K27 acetylation modification of SOD2, resisting oxidative stress, and inhibiting pyroptosis. J SIRT3-mediated deacetylation of NLRC4 at k71 and K272 promotes its activation, which facilitates inflammasome formation and subsequent pyroptosis. K Elevated levels of BRD4 recognize P300-dependent H3K27 acetylation, promoting the expression of the PLK1 gene promoter, strengthening microtubule-organizing center structures, and regulating the subcellular localization of NLRP3 to activate the inflammasome and subsequent pyroptosis. Mitochondrial autophagy also plays an important role in the acetylation regulation of pyroptosis. The PINK1-Parkin-mediated mitophagy can reduce mitochondrial ROS and subsequent activation of the NLRP3 inflammasome. Exogenous Zn²⁺ binds to SIRT1 and significantly inhibits its activity, leading to the upregulation of Parkin acetylation, which promotes mitochondrial autophagy and inhibits NLRP3 inflammasome activation and cellular pyroptosis. During the formation of NLRP3, HSP90 acts as a non-histone substrate of HDAC6, enhancing protein binding capabilities after deacetylation, and can bind to the NLRP3 protein to prevent its degradation and subsequent formation of the NLRP3 inflammasome. GITR competes with NLRP3 for binding to the E3 ubiquitin ligase MARCH7 and recruits MARCH7 to induce the degradation of SIRT2, resulting in decreased ubiquitination of NLRP3 but increased acetylation. This process reduces the degradation of NLRP3 and promotes subsequent pyroptosis. Elevated HDAC2 facilitates the deacetylation of ULK1 at K68, weakening ULK1-mediated autophagy; thus, degradation of NLRP3 is inhibited, driving the occurrence of pyroptosis. Acetylated α-tubulin promotes the dynein-mediated transport of mitochondria (a transport carrier for the NLRP3 inflammasome adapter ASC) along microtubules to the negative end (i.e., the perinuclear region), enhancing the proximity between ASC and NLRP3 on the endoplasmic reticulum and promoting the assembly of the NLRP3 inflammasome. Conversely, the SIRT2 agonist resveratrol and NAD⁺ inhibit the acetylation of α-tubulin, thereby suppressing ASC-mediated assembly and activation of the NLRP3 inflammasome. The regulation of GSDMD protein acetylation involves the p53/GPX4/GSDMD axis, with GSDMD exerting a positive feedback effect on p53. The activation of SIRT1 inhibits the p53/GPX4/GSDMD axis by inducing p53 acetylation, thereby alleviating damage caused by pyroptosis. HDAC4 is responsible for mediating the deacetylation of GSDMD, while the PP1 catalytic subunits PP1α and PP1γ dephosphorylate and inactivate HDAC4, thus promoting acetylation-mediated pyroptosis of GSDMD. HDAC2 histone deacetylase 2, SMAD7 SMAD family member 7, TGF-β transforming growth factor beta, NF-κB nuclear factor kappa B, Erg ETS-related gene (The ETS family comprises a class of transcription factors that recognize and bind to a specific DNA sequence in the promoter regions of target genes, thereby activating or repressing their transcription. Dysregulation of these factors can convert them into potent key oncogenic regulators.), TNF-α tumor pyroptosis factor alpha, ICAM-1 intercellular adhesion molecule 1, HDAC11 histone deacetylase 11, p65 P65 subunit of NF-κB, p50 P50 subunit of NF-κB, IκB inhibitor of kappa B, NLRP3 NOD-like receptor protein 3, HDAC6 histone deacetylase 6, STAT3 signal transducer and activator of transcription 3, EP300 E1A-binding protein p300, P300 E1A-binding protein p300, BRD4 bromodomain-containing 4, KAT5 lysine acetyltransferase 5, STUB1 STIP1 homology and U-box containing protein 1, LATS2 large tumor suppressor kinase 2, NAT10 N-acetyltransferase 10, ULK1 Unc-51 like autophagy-activating kinase 1, STING stimulator of interferon genes, IRF3 interferon regulatory factor 3, GSDMD gasdermin D, HDAC3 histone deacetylase 3, ATG5 ATPase associated with diverse cellular activities 5, VDAC voltage-dependent anion channel, Nrf2 nuclear factor erythroid 2-related factor 2, SOD2 superoxide dismutase 2, SIRT3 sirtuin 3, NLRC4 NLR family CARD domain-containing 4, PLK1 polo-like kinase 1, PINK1-Parkin PTEN-induced kinase 1 and parkin, SIRT1 sirtuin 1, HSP90 heat shock protein 90, HDAC6 histone deacetylase 6, GITR glucocorticoid-induced TNFR family related protein, SIRT2 sirtuin 2, ASC apoptosis-associated speck-like protein containing a CARD, GPX4 glutathione peroxidase 4, HDAC4 histone deacetylase 4, PP1 protein phosphatase 1, PP1α protein phosphatase 1 alpha, PP1γ protein phosphatase 1 gamma.