Lenalidomide triggers ferroptosis in multiple myeloma by blocking the c-Maf/USP7 signaling pathway to induce the ubiquitination and degradation of FTH1.

Multiple myeloma (MM) is the second most common hematological malignancy. Ferroptosis, a distinct form of programmed cell death, has attracted the interest of researchers because of its unique role and biological significance across various diseases. As a first-line clinical treatment drug for MM, lenalidomide (LEN) has shown remarkable therapeutic efficacy. Accumulating evidence has highlighted the significant role of LEN in MM treatment; however, to date, no studies have investigated its potential efficacy in the ferroptosis pathway of MM and the underlying mechanisms. To investigate the therapeutic effects of LEN on MM, several in vitro and in vivo experiments were performed. Our data confirmed that LEN exerts antitumor activity in a dose-dependent manner by inducing ferroptosis, which is characterized by an abnormal increase in ROS and MDA levels, a decrease in GSH levels and mitochondrial membrane potential, and iron overload. Mechanistically, in vitro experiments have revealed that LEN directly targets the c-Maf protein and subsequently suppresses USP7 transcription, thereby inducing FTH1 degradation via the ubiquitin-proteasome pathway, triggering ferroptosis in MM cells. Finally, in vivo experiments demonstrated that LEN (10 mg/kg) significantly suppresses the c-Maf/USP7/FTH1 signaling pathway, further inhibiting MM growth by triggering ferroptosis. In conclusion, this study is the first to demonstrate that LEN suppresses MM by inducing ferroptosis via FTH1-dependent iron homeostasis, suggesting that the ferroptosis induced by the c-Maf/USP7/FTH1 signaling pathway during LEN treatment is a novel mechanism underlying its antitumor activity.