In summary, we show that GSDME-mediated pyroptosis contributes to the development of CAC by releasing intracellular HMGB1, which induces tumor cell proliferation and PCNA expression through the ERK1/2 pathway.Our findings highlight the emerging role of GSDME-mediated HMGB1 secretion in promoting CAC tumorigenesis and provide new insights for the future development of CAC therapeutic strategies by inhibiting GSDME-mediated pyroptosis or using a neutralizing anti-HMGB1 antibody. The gene discussed is MAPK3; the disease is neoplasm.