Abstract: The weightless environment will cause adaptive changes in human physiological functions, in which the remodeling of the structure and function of the heart and blood vessels will lead to the dysfunction of the cardiovascular system, which will have a potential impact on the work efficiency and health of astronauts. Succinylation is a new type of protein post-translational modification, which has been shown to be involved in the development of various cardiovascular diseases. In addition, simulated weightlessness can cause endoplasmic reticulum stress in vascular endothelial cells and a number of studies have found that endoplasmic-reticulum-stress-related signaling pathways are highly correlated with the occurrence and development of many heart diseases. Therefore, this paper summarizes the recent studies on the role of succinylation modification and endoplasmic reticulum stress in cardiovascular dysfunction induced by weightlessness and proposes to combine the studies of the two aspects in order to provide new ideas for the protection of cardiovascular dysfunction under weightlessness.