Periplocin targets STAT3 to suppress MYC expression and inhibit multiple myeloma cell proliferation

OBJECTIVE: Periplocin, a bioactive component derived from the traditional Chinese medicinal herb Periplocae Cortex, has recently emerged as a promising agent for cancer treatment. However, its mode of action, particularly in the context of multiple myeloma (MM), remains poorly characterized. This study investigates the antitumor efficacy of periplocin against MM and elucidates its underlying molecular mechanisms. METHODS: Cell viability was assessed using the cell counting kit-8 assay, while flow cytometry was used to analyze cell cycle distribution and apoptosis rates. The in vivo antitumor effect of periplocin was validated in a murine MM xenograft model. RNA sequencing (RNA-seq) analyses, network pharmacology, molecular docking and cellular thermal shift assay (CETSA) were used to identify potential targets and signaling pathways of periplocin in treating MM. The Gene Expression Profiling database was used to evaluate the correlation between candidate gene expression and survival outcomes in MM patients. A dual-luciferase reporter assay was used to evaluate transcriptional activity, and CUT&Tag polymerase chain reaction (PCR) was used to detect the effect of periplocin on the binding of signal transducer and activator of transcription 3 (STAT3) protein to the Myc proto-oncogene protein (MYC) promoter region. The protein expressions were explored via Western blotting analysis. RESULTS: Periplocin exhibited encouraging anti-MM activity in both cellular and animal models. Periplocin induced MM cell apoptosis and cell cycle blockade. Periplocin prevented the JAK2/STAT3/AKT/mTOR signaling cascade from being activated, impeding MM cell proliferation. Molecular docking and CETSA showed the interaction between periplocin and STAT3. RNA sequencing analysis showed that periplocin regulated STAT3-mediated expression of MYC, whose high expression was closely related to poor prognosis in MM. Moreover, the dual-luciferase reporter assay showed that periplocin significantly suppressed STAT3 transcriptional activity. The CUT&Tag PCR results revealed that periplocin effectively inhibited the binding of STAT3 to the MYC promoter DNA region. Periplocin downregulated MYC expression. CONCLUSION: Periplocin targets STAT3, suppressing MYC expression and leading to the inhibition of MM cell proliferation; this highlights its promise as a novel treatment option for MM. Please cite this article as: Wei RF, Chen JX, Lai SP, Chen ZA, Zhou YY, Liao YP, Chen Y. Periplocin targets STAT3 to suppress MYC expression and inhibit multiple myeloma cell proliferation. J Integr Med. 2026; 24(5):742-752.