Abstract：Objective：To observe the mechanism of action of cantharidin on the proliferation，autophagy，and PKC/ERK signaling pathway in pulmonary artery smooth muscle cells （PASMCs）. Methods：PASMCs were extracted from the lung tissues of two SPF-grade SD rats and the expression of α-SMA was detected by immunohistochemistry. The PASMCs were divided into a control group， a hypoxia group， a low-dose cantharidin group， a medium-dose cantharidin group，and a high-dose cantharidin group. The low-，medium-，and high-dose cantharidin groups were co-cultured with cantharidin at concentrations of 1，5，and 10 μg/mL，respectively. The control group was cultured under normoxic conditions，while the other groups were cultured under hypoxic conditions. Cell viability of PASMCs in each group was detected by MTT assay； apoptosis rate was detected by Hoechst staining； and the expression of autophagy-related proteins Beclin1， LC3B， and PKCβⅠ ， ERK1/2 was detected by Western blot. Results： Immunohistochemical results showed that α-SMA was expressed in the cytoplasm of PASMCs， with over 90% of the cells showing positive expression. The cells had a spindle shape with distinct myofilaments，confirming that they were PASMCs. Compared with the control group，the cell viability of PASMCs in the hypoxia group increased at 24，48，72， and 96 hours （P＜0.05）. Compared with the hypoxia group， the cell viability of PASMCs in the medium- and highdose cantharidin groups decreased at 48，72，and 96 hours（ P＜0.05）. Compared with the low-dose cantharidin group， the cell viability of PASMCs in the medium- and high-dose cantharidin groups decreased at 24， 48， 72， and 96 hours， with a dose-dependent reduction in viability （P＜0.05）. Compared with the control group， the apoptosis rate of PASMCs in the hypoxia group decreased （P＜0.05）， while the protein levels of Beclin1， LC3B， PKCβⅠ， ERK1， and ERK2 increased （P＜0.05）. Compared with the hypoxia group， the apoptosis rate of PASMCs in the medium- and high-dose cantharidin groups increased（ P＜0.05），while the protein levels of Beclin1，LC3B，PKCβⅠ， ERK1， and ERK2 decreased （P＜0.05）. Compared with the low-dose cantharidin group， the apoptosis rate of PASMCs in the medium- and high-dose cantharidin groups increased （P＜0.05），while the protein levels of Beclin1， LC3B，PKCβⅠ，ERK1，and ERK2 decreased （P＜0.05）. Compared with the medium-dose cantharidin group，the apoptosis rate of PASMCs in the high-dose cantharidin group increased （P＜0.05），while the protein levels of Beclin1， LC3B，PKCβⅠ，ERK1，and ERK2 decreased （P＜0.05）. Conclusion：Cantharidin can inhibit the proliferation of PASMCs， under hypoxic conditions by downregulating autophagy and accelerating apoptosis， which is related to the suppression of the PKC/ERK signaling pathway.