Cannabigerol (CBG), a non-psychoactive phytocannabinoid derived from Cannabis sativa , has attracted increasing attention owing to its antibiotic, anti-inflammatory, and anticancer properties. However, its therapeutic potential in pancreatic cancer remains unknown. In this study, we demonstrated for the first time that CBG exerts a potent antiproliferative effect on human pancreatic cancer cells by inducing cell cycle arrest in the G 1 phase and promoting programmed cell death. Transcriptomic profiling revealed that CBG significantly modulates the gene networks involved in apoptosis and ferroptosis. Consistent with these findings, CBG treatment upregulated apoptosis-associated proteins, such as cleaved caspase-3, caspase-9, and PARP1, and increased the proportion of apoptotic cells. CBG triggered robust activation of the unfolded protein response (UPR), with a marked increase in the transcriptional levels of endoplasmic reticulum (ER) stress-related genes. Mechanistically, CBG activated the IRE1α-XBP1 axis, a key branch of the UPR, as evidenced by enhanced XBP1 mRNA splicing. Inhibition of IRE1α by the small-molecule inhibitor 4μ8C substantially mitigated CBG-induced cytotoxicity, emphasizing the central role of ER stress pathways in the mechanism of CBG’s action. Moreover, CBG modulated the expression of ferroptosis-related genes and proteins, such as DDIT3 , NFE2L2 , and HMOX1 , and their respective protein products, CHOP, NRF2, and HO-1. These findings reveal a novel mechanism by which CBG concurrently induces apoptosis and ferroptosis via ER stress-driven activation of the IRE1α pathway, supporting its potential as a therapeutic agent targeting ER stress-related vulnerabilities in pancreatic cancer. • CBG upregulates apoptosis proteins including caspase-3, caspase-9, and PARP1. • CBG activates the unfolded protein response and ER stress in cancer cells. • CBG selectively activates the IRE1α–XBP1 branch of the UPR. • IRE1α inhibition reduces CBG-induced cytotoxicity in pancreatic cancer cells. • CBG alters ferroptosis-related genes such as DDIT3, NFE2L2, and HMOX1. • CBG induces apoptosis and ferroptosis via ER stress–driven IRE1α activation.
Park et al. (Sun,) studied this question.