8-gingerol from Zingiber officinale induces ER stress-mediated ferroptosis and apoptosis in ovarian cancer involving TRPV1 activation.

BACKGROUND: Ovarian cancer remains among the most lethal gynecological malignancies, primarily due to the persistent challenges of chemotherapy resistance and limited effectiveness of existing therapeutic strategies.

METHODS: To evaluate the anti-tumor activity of 8-gingerol, its effects on cell viability, glutathione (GSH) levels, and the activities of caspase-3, lactate dehydrogenase (LDH), reactive oxygen species (ROS), and malondialdehyde (MDA) were examined in ovarian cancer cell lines. The underlying molecular mechanisms were investigated, involving the analysis of the TRPV1-PLCγ-NOX4 and PERK-ATF3-JMJD2C-SLC7A11-GPX4 signaling pathways. The functional role of ATF3 was further validated using gene knockdown approaches and promoter-binding assays. In addition, the in vivo therapeutic efficacy of 8-gingerol was assessed using a xenograft mouse model.

RESULTS: Treatment with 8-gingerol significantly reduced cell viability and intracellular GSH levels, while increasing caspase-3 activity, LDH release, ROS generation, and MDA levels. These molecular and cellular effects were associated with marked inhibition of tumor growth in vivo. Mechanistically, 8-gingerol induced intracellular Ca2+ accumulation and ROS production, thereby promoting endoplasmic reticulum (ER) stress-mediated apoptotic and ferroptotic cell death. This process was mediated in a manner involving activation of the TRPV1-PLCγ-NOX4 axis and ATF3-dependent suppression of SLC7A11 via the histone demethylase JMJD2C. Importantly, pharmacological inhibition of ROS or genetic targeting of ATF3 significantly attenuated 8-gingerol-induced cell death, confirming the critical functional roles of these signaling pathways.

CONCLUSIONS: These findings demonstrate that 8-gingerol induces coordinated apoptotic and ferroptotic cell death through a Ca2+-dependent ER stress mechanism, highlighting its potential as a novel therapeutic strategy for the treatment of ovarian cancer.