Kaempferide Inhibits the Proliferation and Invasion and Induces Ferroptosis in Melanoma by Inactivating Wnt/β‐Catenin Pathway

Melanoma is a type of skin cancers, with the nature of aggression, metastasis and high lethality. Kaempferide (KF), a natural flavonoid, shows anti-cancer in different cancers. However, the activity of KF on melanoma remains unclear. Cell counting kit-8, transwell, iron measurement, the determination of ROS levels and western blot were utilized to examine the impact and mechanism of KF on melanoma. An in vivo investigation employing immunohistochemistry and western blot assays was carried out on tumor-bearing mice. A375 and A2085 cells' E-cadherin expression was boosted whereas N-cadherin expression, invasion count, and cell survival were all decreased by KF. In both A375 and A2085, KF raised the relative Fe²⁺ level, which was then farther enhanced by the erastin incubation and reduced by the ferrostatin-1 treatment. Besides, KF enhanced the level of ROS while lowering the expression of xCT and GPX4 in the two cells. Mechanically, the application of LiCl reversed the drop in the relative levels of p-GSK3β/GSK3β, c-Myc, and active-β-catenin/β-catenin in melanoma cells caused by KF. LiCl's activation of the Wnt/β-catenin pathway counteracted the impact of KF on melanoma cell proliferation, invasion, and ferroptosis. KF reduced tumor weight and volume in vivo, as well as the expression of c-Myc, p-GSK3β/GSK3β, active-β-catenin/β-catenin, and N-cadherin, GPX4, and xCT, but enhanced the E-cadherin level in mice xenografted with A375 cells. KF inhibited melanoma by attenuating proliferation and invasion and inducing ferroptosis via Wnt/β-catenin axis, highlighting the underlying therapeutical effect of KF on melanoma.