MYC-SNHG7-miR-34a-5p Feedback Loop Orchestrates GSDMD-Dependent Pyroptosis in Hepatocellular Carcinoma.

Pyroptosis is an immunogenic form of regulated cell death mediated by NLRP3 inflammasome activation, caspase-1, and gasdermin D. Unlike apoptosis, pyroptosis promotes anti-tumor immunity through IL-1β and IL-18 release, making it a promising therapeutic target in hepatocellular carcinoma (HCC). Although the SNHG7/miR-34a/SIRT1 axis has been experimentally linked to NLRP3-dependent pyroptosis, whether it functions as a systems-level regulatory module coordinating the balance between drug resistance and multiple cell-fate outcomes remains unknown. To address this question, we developed a network medicine framework using a Boolean network model integrating drug resistance, senescence, apoptosis, and pyroptosis pathways in HCC. The model was constructed from experimentally validated molecular interactions and independently validated using gain- and loss-of-function perturbation studies that were not used during model construction, demonstrating strong agreement with experimental observations. Our analysis identified a previously unreported MYC-SNHG7-miR-34a double-negative feedback loop, establishing miR-34a as a central regulatory hub controlling cell-fate decisions. Perturbation analysis predicted that SNHG7 inhibition shifts cells from drug resistance toward pyroptosis, identifying restoration of miR-34a activity as a potential strategy to induce immunogenic cell death. These findings provide a systems-level framework for therapeutic targeting of the MYC-SNHG7-miR-34a axis in HCC.