Icaritin Inhibits Malignant Progression and Enhances Ferroptosis and Bortezomib Sensitivity by Suppressing HSP90AA1 Expression in Multiple Myeloma

ABSTRACT Multiple myeloma (MM) is a hematologic malignancy commonly treated with bortezomib (BTZ). However, treatment efficacy is often limited by the development of BTZ resistance. Icaritin has demonstrated broad anti‐tumor activities. This study aimed to investigate the effect of Icaritin on the malignant progression of MM and its potential to overcome BTZ resistance. The anti‐MM activity of Icaritin was evaluated through a series of experimental approaches, including cell counting kit 8, flow cytometry, 5‐ethynyl‐2′‐deoxyuridine, network pharmacology, molecule docking, reverse transcription‐quantitative polymerase chain reaction, Co‐Immunoprecipitation (CoIP), and western blot. Icaritin suppressed MM cell viability and proliferation, induced ferroptosis, and enhanced cellular sensitivity to BTZ. Moreover, Icaritin inhibited HSP90α family 1 (HSP90AA1) protein expression via promoting ubiquitination. HSP90AA1 facilitated MM cell proliferation, suppressed ferroptosis, and attenuated BTZ sensitivity. Notably, Icaritin promoted MM cell ferroptosis and BTZ sensitivity by inhibiting HSP90AA1. In vivo, Icaritin enhanced the sensitivity of tumor cells to BTZ. Icaritin suppresses malignant progression, induces ferroptosis, and enhances BTZ sensitivity in MM by inhibiting HSP90AA1. These findings provide a novel theoretical basis for Icaritin treatment of MM and regulation of BTZ sensitivity.