Abstract Background Stroke is a cerebrovascular disease that is the main cause of death and disability worldwide. Hypoxia is a major factor that causes neuronal damage and even cellular death. However, the mechanism and therapeutic drugs for hypoxia are not completely understood. Methods In this study, PC12 cells (a rat adrenal pheochromocytoma cell line) were exposed to Cobalt chloride (CoCl2) to induce hypoxia. Using this cell model, the impacts of hypoxia on cell viability, proliferation, reactive oxygen species (ROS), and the levels of lysine β-hydroxybutyrylation (Kbhb) and the inflammatory signaling factor P65 were examined. In addition, we explored the ability of resveratrol (RES) to alleviate CoCl2-induced hypoxia damage. Results RES attenuated CoCl2-induced decreases of cell viability and cell proliferation and increase of ROS production in PC12 cells. CoCl2 downregulated Kbhb in PC12 cells, but RES alleviated this effect. In addition, upregulated Kbhb by 3-hydroxybutyric acid sodium could partially recover the CoCl2-induced hypoxia damage to PC12 cells, including cell viability, cell proliferation, oxidative stress, and the protein level of the inflammatory signaling factor P65. Conclusion Our results indicate that RES protects against CoCl2-induced hypoxia damage in PC12 cells by modulating Kbhb, a novel post-translational modification.
