Repurposing Hetrombopag for Multiple Myeloma by Targeting PNPO: A Celastrol‐Inspired Approach

Multiple myeloma (MM) is a malignancy of plasma cells whose excessive immunoglobulin production elevates reactive oxygen species (ROS), promoting pathogenesis. Active compounds from Traditional Chinese Medicine, such as celastrol, can exert antitumour effects by further increasing ROS levels to toxic levels, thereby inducing apoptosis. Our previous study has demonstrated that pyridoxine‐5′‐phosphate oxidase (PNPO) is the specific target of celastrol. In this study, we discovered that PNPO, a key enzyme involved in vitamin B6 coenzyme metabolism, is highly expressed in various cancers, including MM. Increased PNPO levels correlated with MM disease progression, promoting cell proliferation and inducing osteoclast differentiation via exosomes. Concurrently, through a structure‐based virtual screening workflow targeting critical PNPO residues (R95 and K117), we identified Hetrombopag as a potential PNPO inhibitor. Hetrombopag simultaneously inhibited MM cell proliferation and osteoclast differentiation. Preliminary data from clinical trials also supported the idea that hetrombopag treatment can prolong survival in MM patients. Our research highlights the significant role of PNPO in MM progression and suggests hetrombopag as a promising therapeutic option for MM treatment.