Epigenetic regulation of PANoptosis: DNA methylation, histone modifications and non-coding RNAs.

PANoptosome (Programmed Necrosis-Apoptosis Optosome) multiprotein complexes mediate the convergence of apoptosis, pyroptosis, and necroptosis. The ability of cells to undergo programmed inflammatory cell death is regulated by the epigenetic control of PANoptotic sensors, adaptors, and effectors, and has pivotal implications for their use in cancer therapies. DNA methylation suppresses the main PANoptotic pathways, such as RIPK3 (Receptor-Interacting Serine/Threonine-Protein Kinase 3), GSDME (Gasdermin E), and CASP8 (Caspase-8) that promote chemoresistance; hypomethylating DNA silencers resume PANoptotic sensitivity. BRD4 (Bromodomain-Containing Protein 4)/p300 (E1A-Associated Protein p300 - Histone Acetyltransferase) -mediated histone acetylation in enhancers (H3K27ac) stimulates ZBP1 (Z-DNA Binding Protein 1), NLRP3 (NOD-Like Receptor Family Pyrin Domain Containing 3), and caspase-8 transcription but inhibits the formation of inflammasomes by HDAC (Histone Deacetylase). PANoptotic regulatory regions become accessible in response to inflammatory signals through the dynamic regulation of accessibility through the SWI/SNF (Switch/Sucrose Non-Fermentable Chromatin Remodeling Complex) and NuRD (Nucleosome Remodeling Complex) and NuRD (Nucleosome Remodeling and Deacetylase Complex) chromatin remodelling complexes. Post-transcriptional regulation is mediated by ncRNAs (ncRNAs) such as miR-223-3p (MicroRNA-223-3p) and lncRNA NEAT1 (Long Non-Coding RNA - Nuclear Enriched Abundant Transcript 1) which converge to regulate the expression of NLRP3, RIPK3, and Gasdermin D (GSDMD). The interaction of DNA methylation, histone modification, and ncRNAs creates quantitative epigenetic thresholds that regulate PANoptotic sensitivity. The rational next step to overcome tumor immunoresistance is epigenetic biomarker stratification in combination with DNA methyltransferase inhibitors (DNMTi), histone deacetylase modulators (HDACi), and PANoptosis agonists, which could help reduce collateral tissue toxicity. See also the graphical abstract(Fig. 1).