Fig. 1: Nuclear regulatory mechanisms driving tumor cell pyroptosis through transcriptional control of pyroptosis-associated proteins.

Extracellular HMGB1 activates TLRs to promote NF-κB translocation and DNA binding. SIRT1 sustains NF-κB expression in neoplastic cells (MCF-7/H1299). BRD4 synergizes with NF-κB to transcribe pro–IL-1β and NLRP3 and partners with IRF8 to expand neuronal apoptosis inhibitor protein (NAIP)/NLR family CARD domain-containing protein 4 (NLRC4) inflammasome diversity. IRF1 compensates for IRF2 deficiency in regulating GSDMD expression; IRF1 promotes AIM2 during Francisella infection, whereas IRF2 preferentially induces caspase-4, and both may enhance GSDMB expression. p53 directly activates caspase-1 and GSDME transcription. ATF4 upregulates CHOP, which subsequently drives caspase-1–mediated GSDMD cleavage. Under hypoxia, nuclear PD-L1 associates with phosphorylated STAT3 (Y705) to form a transcriptional complex that engages STAT3 response elements within the GSDMC promoter. Collectively, NRF2, STAT6, NF-κB, HMGB1, SIRT1, BRD4, IRF5, p53, and ATF4, collaboratively regulate the transcription of pyroptosis-related executors and inflammasome components. These include GSDM family members (GSDMD, GSDMC, GSDMB, GSDME), caspases (caspase-1, caspase-4), pro-inflammatory cytokine precursors (Pro-IL-1β, Pro-IL-18), and inflammasome sensors (NLRP3, NAIP, NLRC4). These molecular events orchestrate pyroptosis through membrane pore formation and inflammatory cascade activation.