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

Abstract 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 Ca 2+ 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 Ca 2+ -dependent ER stress mechanism, highlighting its potential as a novel therapeutic strategy for the treatment of ovarian cancer.