[Research progress in antitumor molecular mechanisms of bufadienolides in Bufonis Venenum]

Bufonis Venenum, the dried secretory product from the postauricular and cutaneous glands of Bufonidae, exerts antitumor activity primarily through bufadienolides. This review systematically summarizes the molecular mechanisms of key bufadienolides, including cinobufagin, bufalin, resibufogenin, bufotalin, arenobufagin, gamabufotalin, and cinobufotalin, in the treatment of malignant tumors over the past five years. Current evidence demonstrates that these compounds exert broad-spectrum antitumor effects through multi-target and multi-pathway modulation. In inhibiting tumor cell proliferation, these compounds primarily regulate signaling pathways such as mitogen-activated protein kinase(MAPK), phosphatidylinositol-3-kinase/protein kinase B(PI3K/AKT), and signal transducer and activator of transcription 3(STAT3). In inducing cell death, they eliminate malignant cells through multiple modalities including mitochondrion-mediated apoptosis, ferroptosis, and autophagy. In suppressing invasion and metastasis, they modulate epithelial-mesenchymal transition(EMT), matrix metalloproteinase(MMP) expression, and macrophage polarization within the tumor microenvironment. Furthermore, these compounds inhibit angiogenesis, enhance chemosensitivity, activate antitumor immune responses, and regulate epigenetic modifications. Combination therapy studies reveal that bufadienolides exhibit synergistic efficacy when being combined with clinical chemotherapeutic agents, and TCM preparations containing these compounds demonstrate antitumor properties through multi-target regulation. This review elucidates the antitumor molecular mechanisms of bufadienolides, aiming to provide a theoretical basis for further mechanism investigation and clinical translation.