Cordycepin suppresses the progression of multiple myeloma by inducing ferroptosis through upregulating CLEC2.

Multiple myeloma (MM) is a clonal plasma cell disorder and is the second most common hematologic malignancy worldwide. In recent years, ferroptosis has emerged as an important target for cancer therapy, including MM. Cordycepin (COR) is a nucleoside antibiotic that was first isolated from fungi, with potential anti-tumor properties. The current research elucidated the therapeutic mechanism against MM of COR by investigating its effects on ferroptosis. U266 or NCI-H929 cells were incubated with COR (1, 3, and 10 µM) for 24 h, respectively. In both U266 and NCI-H929 cells, dramatically declined cell viability, reduced migrated cell counts, increased ROS productions and MDA levels, and repressed SOD activities were observed following COR incubation. Furthermore, in COR-treated U266 or NCI-H929 cells, markedly increased Fe(2+) levels, upregulated ACSL4, and downregulated GPX4 were induced by COR, accompanied by an inhibition of HIF-1α/SLC7A11 axis and an upregulation of CLEC2. To confirm the role of ferroptosis and CLEC2 in COR's anti-tumor function, U266 cells were treated by COR for 24 h, followed by incubation with Fer-1 or transfected with si-CLEC2. The decreased cell viability, reduced migrated cells, increased ACSL4 levels, downregulated GPX4, and inhibited HIF-1α/SLC7A11 axis in COR-treated U266 cells were remarkably reversed by Fer-1 or silencing CLEC2. In addition, inhibitory effects of COR on the growth of U266 xenograft model, as well as facilitating effects of COR on ferroptosis in U266 xenograft tumor tissues, were reversed by Fer-1 or silencing CLEC2. Collectively, COR inhibited MM progression by inducing ferroptosis through upregulating CLEC2. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10616-025-00886-5.