Pristimerin Suppresses Janus Kinase/Signal Transducers and Activators of Transcription Oncogenic Signaling To Drive Mitochondrial and Caspase-Dependent Apoptosis in Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell malignancy characterized by uncontrolled clonal expansion within the bone marrow, and despite major therapeutic advances, it remains largely incurable. The identification of novel agents capable of overcoming apoptosis resistance and targeting critical survival pathways is therefore essential. This study explored in vitro the anticancer potential of pristimerin (Prist), a natural quinone methide triterpenoid, in MM. Prist significantly inhibited the viability of U266 and RPMI8226 cells in a dose-dependent manner and induced cell cycle arrest in the SubG0/G1 phase, indicating apoptotic cell death. Mechanistic studies revealed that Prist triggers apoptosis via caspase cascade activation and targets the JAK/STAT signaling pathway, a critical oncogenic driver in MM. Network pharmacology and molecular docking suggests Prist's plausible binding with the STAT3 active site, a key component of the JAK/STAT pathway, supporting its inhibitory role. Western blot analysis demonstrated that Prist reduced the constitutive phosphorylated STAT3 (p-STAT3) as well as IL6- IL6-stimulated p-STAT3 levels in MM cells, further validating STAT3 pathway inactivation. Importantly, Prist synergistically enhanced the cytotoxic effects of bortezomib, further amplifying caspase activation and apoptotic signaling. Collectively, these findings identify Prist as a potent natural compound that suppresses MM progression by inducing apoptosis and blocking STAT3-driven oncogenic signaling. This study highlights Prist's therapeutic promise and supports its further evaluation as a standalone or combination strategy for MM treatment.