Abstract
Cardiovascular diseases (CVDs) represent a major public health concern globally, being one of the leading causes of illness and death across populations. While physical activity is widely recognized as a protective factor against these diseases, the exact biological mechanisms that explain this relationship are still not fully understood. This study utilized a two-sample Mendelian randomization (MR) method to investigate the potential role of circulating cytokines in mediating the effects of physical activity on major CVD outcomes, including coronary artery disease (CAD), heart failure (HF), and ischemic heart disease (IHD). Our primary MR analysis revealed an inverse association between physical activity and IHD risk. Moreover, a two-step MR mediation approach identified IL10RB (Interleukin-10 receptor subunit beta) as an intermediate mediator, explaining about 6.65% of the observed contribution of physical activity to IHD. These results indicate that physical activity may mitigate CVD risk through modulation of immune pathways, particularly via IL10RB signaling. Our findings underscore the significance of cytokine networks in mediating the cardiovascular benefits of exercise and suggest potential therapeutic strategies for CVD risk reduction through immune system modulation.