Cannabigerol induces endoplasmic reticulum stress-mediated apoptosis and ferroptosis via the IRE1α-XBP1 axis in human pancreatic cancer cells.

Abstract

<p>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 G1 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.</p>