Ginsenoside Compound K Inhibits Pancreatic Cancer by Induction of Canonical Pyroptosis Associated with HAPLN1 Signaling

Background: Pancreatic cancer (PC) remains one of the most lethal malignancies because of its highly immunosuppressive tumor microenvironment and profound resistance to current therapies. Increasing evidence suggests that pyroptosis, a pro-inflammatory form of programmed cell death, may provide a promising strategy for enhancing anti-tumor immunity and improving therapeutic responsiveness. Ginsenoside Compound K (CK), a major bioactive intestinal metabolite of Panax ginseng, exhibits diverse pharmacological and anti-tumor activities. However, whether its anti-PC effects involve the induction of tumor cell pyroptosis remains unclear. Methods: The anti-tumor effects and underlying mechanisms of CK were investigated in Panc02 tumor-bearing mice and BxPC-3 pancreatic cancer cells. Tumor growth, systemic toxicity, pyroptosis-related events, reactive oxygen species (ROS) production and the involvement of the HAPLN1–TNFα/NF-κB signaling pathway were evaluated. Pharmacological inhibition of ROS and caspase-1 was employed to verify the mechanism of CK-induced pyroptosis. Results: CK significantly suppressed tumor growth without causing apparent systemic toxicity and induced characteristic pyroptotic changes, including caspase-1 activation, enhanced lactate dehydrogenase release, and disruption of mitochondrial membrane potential. Mechanistically, CK promoted intracellular ROS accumulation and activated the HAPLN1–TNFα/NF-κB axis, leading to NLRP3 inflammasome activation and subsequent cleavage of caspase-1 and gasdermin D (GSDMD). And either ROS scavenging or caspase-1 inhibition markedly attenuated CK-induced pyroptosis. Conclusions: CK exerts potent anti-pancreatic cancer activity by promoting ROS/NLRP3-dependent pyroptosis and is associated with HAPLN1-related inflammatory signaling, supporting its further development as a therapeutic candidate for pancreatic cancer.