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. 2022 Mar 8;13:865073. doi: 10.3389/fgene.2022.865073

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Copyright © 2022 Feng, Zhou, Huang, Lin, Zeng, Han, Huang, Liu, Zhu, Yuan and Liang.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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A proposed model illustrating that nobiletin induces ferroptosis in melanoma cells. Nobiletin increases the expression of GSK3β, which activates Keap1 and inhibits the Nrf2/HO-1 axis. Nobiletin leads to the accumulation of iron and ROS. In another side, inhibiton of Keap1/Nrf2/HO-1 axis suppresses GSH, and then inactivates GPX4. Both ROS accumulation and GPX4 inactivation give rise to lipid peroxidation, thereby inducing ferroptosis. In summary, nobiletin induces ferroptosis by regulation of the GSK3β-mediated Keap1/Nrf2/HO-1 signaling pathway in human melanoma cells.