P-glycoprotein 1 as a shared target for resensitizing drug-resistant tumor cells and preventing fibronectin-driven metastasis.

Rationale: The exacerbation of chemoresistance and metastasis by synthetic cytotoxic reagents hinders effective cancer therapy, as these events often coincide and lead to poor clinical outcomes, yet are rarely targeted through a shared molecular mechanism. To address this, we established a mechanism-informed natural compound discovery strategy to identify a non-cytotoxic candidate with dual functionality, namely re-sensitizing drug-resistant tumor cells and preventing metastasis. Methods: Western blot, RT-qPCR, and flow cytometry were used for evaluating protein and mRNA expression, as well as cell apoptosis, while GC/MS and HPLC analyses for identifying active phytochemicals from extracts of traditional Chinese medicines. Therapeutic potential was validated in multiple mouse cancer models, including K-ras Results: Mulberroside A (Mul A) from Conclusions: These findings identify Mul A as a promising non-cytotoxic therapeutic candidate and elucidate the shared upstream molecular mechanism linking distinct downstream chemoresistance and metastasis.