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Moderate intensity exercise is considered as a primary step to prevent coronary artery diseases (CADs) by stimulated FSTL-1 secretion as a novel myokines to improve endothelial cell function, prevent arterial stiffness, or vascular inflammation. This review aims to provide the current evident role of FSTL-1 as a novel myokine secreted during exercise to prevent atherosclerosis progression. A systematic review using databases from (PubMed), ScienceDirect, and The Cochrane Library, was conducted up to October 2021 to identify all the eligible experimental and observational studies that assess how moderate intensity exercises stimulate FSTL-1 secretion to prevent atherosclerosis. Results were described through narrative synthesis of the evidence. From 84 retrieved references, 15 studies met the inclusion criteria and were included in this review. The overall results suggest that exercise or physical activity can stimulate myokines secretion, especially in FSTL-1. FSTL-1 is a myokine or adipokine that plays a potential role in preventing atherosclerosis by various mechanisms such as via improvement of endothelial functions, suppression of smooth muscle cells (SMCs) proliferation, and reduction of arterial thickening. FSTL-1 is a relatively new and less known myokine, but probably holds a key role in assessing how moderate intensity aerobic exercise prevents atherosclerosis progression by preventing endothelial dysfunction, arterial stiffness, or vascular inflammation., Competing Interests: Conflict of Interest None declared., (International College of Angiology. This article is published by Thieme.)