Compound Kushen Injection suppresses multiple myeloma progression via TOP1-targeted coordination of DNA damage and endoplasmic reticulum stress.

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable due to inevitable relapse and poor treatment tolerance. Compound Kushen Injection (CKI), a traditional Chinese medicinal formulation, has been reported to exert anti-tumor effects in various cancers, but its efficacy and mechanisms in MM remain unclear. This study aimed to elucidate the anti-MM mechanisms of CKI, focusing on its induction of DNA damage response (DDR) and endoplasmic reticulum (ER) stress, and to assess synergy with proteasome inhibitors (PIs). Anti-MM efficacy of CKI was evaluated in MM cell lines, primary CD138+ patient-derived cells, and xenograft models. Mechanistic investigations integrated network pharmacology and transcriptomic profiling, with further validation through molecular docking, cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), and Western blot. Synergy between CKI and PIs was assessed using SynergyFinder V3. CKI suppresss MM proliferation in vitro and in vivo, inducing apoptosis and G0/G1 cell cycle arrest. Mechanistically, CKI targetes topoisomerase I (TOP1) to trigger DDR. TOP1 also activates PERK/ATF4-dependent ER stress pathway, bypassing p53 signaling and inducing cytotoxicity in TP53-mutant cells. Synergy analysis indicates that CKI enhanced the efficacy of PIs by increasing DNA damage and ER stress. In xenograft models, combining CKI with bortezomib reduced tumor burden and prolonged survival without significant myelosuppression. CKI exerts anti-MM effects by targeting TOP1 to induce DDR and ER stress, and synergizes with PIs. These results suggest the potential of CKI as a chemosensitizing adjuvant for MM.