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Published on: May 10, 2024
19-Hydroxybufalin Inhibits Gastric Cancer Cell Proliferation by Modulating Metabolic Reprogramming
Xiao Liang1,2, Yilin Liu1, Xiaoting Ma3
1Department of Gastrointestinal Oncology, Jiangyin Clinical College of Xuzhou Medical University, Jiangyin 214400, China.
Objective:
19-Hydroxybufalin (19-H) is a natural bioactive compound with anticancer potential, but its molecular target and mechanism of action remain unclear. This study aimed to systematically evaluate its antigastric cancer activity and identify potential molecular targets.
Methods:
The antitumor effect of 19-H was evaluated in both in vitro and in vivo models. Multiomics analysis, thermal proteome profiling, molecular docking, and molecular dynamics simulations were employed to elucidate the mechanism of action. Functional assays were further conducted to validate the key target.
Results:
19-H exhibited nanomolar-level inhibitory activity against various gastric cancer cell lines, significantly suppressing tumor growth in subcutaneous xenograft and patient-derived xenograft models. Multiomics analysis revealed that 19-H reshaped metabolic pathways in gastric cancer. TPP screening identified PLPP2 as a potential target with significantly increased thermal stability upon 19-H treatment. Molecular simulations further revealed that 19-H binds stably to the α-helical region of PLPP2.
Conclusions:
19-H exerts its antigastric cancer effect by targeting PLPP2 and remodeling the metabolic network. PLPP2 may represent a novel therapeutic target for gastric cancer.
