Arteannuin B targets HSP90 to regulate the AKT/NRF2 axis and induce ferroptosis in cervical cancer cells, exerting antitumor effects

<p indent="0mm">Arteannuin B (Art-B), a sesquiterpene lactone derived from the traditional Chinese medicinal herb <italic>Artemisia annua</italic>, exhibits significant antitumor effects. However, the precise mechanism underlying its action remains unclear. This study investigates the mechanism of Art-B-induced ferroptosis in cervical cancer (CC). Our findings demonstrate that Art-B directly targets HSP90, disrupts its interaction with AKT and further inhibits AKT phosphorylation. This inhibition induces the upregulation of Keap-1 and suppresses NRF2 activity by impeding its nuclear translocation, thereby reducing its transcriptional activity. Consequently, the expressions of key antioxidant proteins, GPX4 and SLC7A11, are downregulated. These molecular alterations lead to a decrease in intracellular GSH levels along with the accumulation of ferrous ions (Fe²⁺), lipid ROS, and MDA, ultimately triggering ferroptosis in CC cells. Additionally, Art-B significantly inhibits the growth of nude mouse xenograft tumors without causing observable toxicity. This study presents the report of Art-B-induced ferroptosis in CC through modulation of the HSP90/AKT/NRF2 signaling axis, offering a novel therapeutic approach for CC.