Wedelolide A induces ferroptosis and apoptosis in gastric cancer via keap1/Nrf2 modulation and ROS generation.

Gastric cancer (GC) is a major global health challenge, with conventional chemotherapy facing significant limitations due to resistance and severe side effects. Natural products are promising alternatives, and in this study, we explore the antitumor effects of Wedelolide A (WA), a sesquiterpene lactone isolated from Sphagneticola trilobata. We showed that WA inhibits gastric cancer cell proliferation through both apoptosis and ferroptosis. WA-induced apoptosis was characterized by caspase activation, cleavage of PARP1, and an altered BCL-2/BAX ratio. In parallel, WA triggered ferroptosis by generating excessive reactive oxygen species (ROS), leading to lipid peroxidation and a marked reduction in the antioxidant defenses, notably through inhibition of the System Xc-/GPX4 axis. Importantly, WA activated the Keap1/Nrf2/HO-1 pathway, with Nrf2 activation further promoting the cell death response. Western blot and transcriptomic analyses revealed that WA modulates ferroptosis-related proteins, including SLC7A11 and GPX4, while activating the Keap1/Nrf2 pathway. In vivo, WA inhibited tumor growth in xenograft models without causing severe toxicity, indicating its potential as a therapeutic agent for GC. Taken together, these findings suggest that WA exerts potent antitumor activity by inducing both apoptosis and ferroptosis through oxidative stress, mitochondrial dysfunction, and the Keap1/Nrf2/HO-1 pathway, positioning it as a promising candidate for gastric cancer therapy.