Downregulation of CLEC2 Facilitates the Proliferation and Migration of Multiple Myeloma Cells via Regulating HIF‐1α‐Mediated Ferroptosis

Multiple myeloma (MM) is a hematologic cancer affecting plasma cells, characterized by the abnormal proliferation of malignant plasma cells in the bone marrow. Research in recent years has shown that the inhibition of ferroptosis is involved in the pathogenesis of MM. CLEC2 is a C-type lectin receptor family member mainly related to the activation of platelets, which is reported to be lowly expressed in multiple tumors. However, the role of CLEC2 in MM remain unknown. The present study clarified CLEC2's function in MM by exploring its impacts on ferroptosis. Comparing to normal plasma cells (NPCs), CLEC2 was found markedly downregulated in MM cell lines. In CLEC2-overexpressed U266 cells, largely declined cell viability and migrated cell counts, markedly enhanced ROS and MDA levels, and declined SOD activities were observed, accompanied by increased Fe²⁺ levels, upregulated ACSL4, and downregulated GPX4, HIF-1α, and SLC7A11. Moreover, in CLEC2-knockdown OPM-2 cells, greatly increased cell viability and migrated cell counts, sharply repressed ROS and MDA levels, and enhanced SOD activities were observed, along with reduced Fe²⁺ levels, downregulated ACSL4, and upregulated GPX4, HIF-1α, and SLC7A11. In addition, influences of CLEC2 overexpression on proliferation, Fe²⁺ levels, and expressions of ACSL4, GPX4, HIF-1α, and SLC7A11 in U266 cells were remarkably abolished by Fer-1 (an inhibitor of ferroptosis) or HIF-1α overexpression. Collectively, downregulation of CLEC2 in MM facilitated the proliferation and migration of MM cells via regulating HIF-1α-mediated ferroptosis.