Targeting FOXM1 regulates metabolic signatures through ROS-dependent JNK/Bmi1/Skp2 axis in human cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a progressive and heterogeneous malignancy characterized by deregulated metabolic reprogramming and cancer stemness, with limited therapeutic options. Therefore, elucidating the mechanisms driving metabolic reprogramming and poor clinical outcomes in CTCL is imperative. Forkhead box protein M1 (FOXM1), an oncogenic transcription factor, plays a pivotal role in cancer pathogenesis by orchestrating metabolic reprogramming and stemness signaling, thereby contributing to therapeutic resistance. In this study, we investigated the therapeutic potential of FOXM1 inhibition in human CTCL cells. Both genetic and pharmacological targeting of FOXM1 markedly suppressed CTCL cell growth and proliferation by inducing programmed cell death (apoptosis and autophagy) via reactive oxygen species (ROS) generation. Mechanistic analyses revealed that the activation of the MAPK, particularly JNK activation, is crucial for thiostrepton-induced programmed cell death. Metabolomics profiling further demonstrated that thiostrepton treatment triggers ROS- and JNK-dependent alteration in metabolic pathways central to cancer hallmarks, including amino acid and lipid metabolism. Notably, FOXM1 inhibition abrogated stemness-associated metabolic reprogramming genes (KLF-4, Bmi1) and Skp2, while upregulating the tumor suppressor p21 in a JNK-dependent manner. Moreover, thiostrepton treatment sensitized the CTCL cells to proteasome inhibitor bortezomib, promoting apoptosis and autophagy. Collectively, these findings demonstrate that FOXM1 targeting disrupts the metabolic status and stemness features of CTCL cells via JNK activation, thereby offering novel insights into potential therapeutic strategies for overcoming therapeutic challenges in CTCL.