Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, with a high recurrence rate and heterogeneity. We aimed to examine the effect of corosolic acid (CRA) on HCC. We employed transcriptomics to validate the target molecules in CRA-treated HCC cells and conducted enrichment analyses that revealed their involvement in the regulation of endoplasmic reticulum (ER) stress and apoptosis. Our experimental data indicated that CRA markedly induced apoptosis in human HCC cell lines through the mitochondrial apoptosis pathway. We also revealed that the pro-apoptotic effects of CRA depended on ER stress, as pretreatment with selective ERS inhibitor salubrinal effectively reversed CRA-induced cell apoptosis. Furthermore, the knockdown of the unfolded protein response (UPR) protein CHOP remarkably abrogated CRA-induced expression of ER stress-associated proteins. Collectively, our results suggest that CRA triggers ER stress-mediated apoptosis in HCC cells via activation of the PERK-eIF2a-ATF4 pathway. Our findings provide novel insights into the potential therapeutic strategies for HCC.
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We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript.
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This work was supported by the National Natural Science Foundation of China (grant no. 81873150), and the Innovative project of the Health Commission of Shanghai Municipality (ZY (2021-2023)-0203-04).
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Yanfeng Xu and Feifeng Tang contributed to the conception and design of the study; Feifeng Tang and Yingxiu Peng performed the experiments; Feifeng Tang contributed to the acquisition, analysis, and interpretation of data; Feifeng Tang drafted the manuscript; Yanfeng Xu supervised the project; Jingjin Liu and Wenhui Gao were involved in the investigation; Yanfeng Xu revised the manuscript critically for important intellectual content. All authors have approved the final vision of this manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Tang, F., Peng, Y., Liu, J. et al. Integrating network pharmacology and experimental models to examine the mechanisms of corosolic acid in preventing hepatocellular carcinoma progression through activation PERK-eIF2a-ATF4 signaling. Naunyn-Schmiedeberg's Arch Pharmacol 396, 3671–3682 (2023). https://doi.org/10.1007/s00210-023-02560-z
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DOI: https://doi.org/10.1007/s00210-023-02560-z