Multiomics profiling identifies molecular and cellular signatures of regular exercise in human peripheral blood.

Regular exercise is well established to protect against metabolic disorders and bolster immunity, but the underlying molecular and cellular mechanisms remain incompletely understood. We integrated plasma metabolomics and lipidomics with single-cell transcriptomic and chromatin accessibility profiles from regularly exercising versus sedentary individuals. We observed that regular exercise was associated with enhanced fatty acid oxidation and antioxidant metabolites in plasma. In the circulating immune cells of exercising individuals, antigen-presenting cells (APCs), particularly classical monocytes and B cells, showed concordant increases in both chromatin accessibility and transcription of antigen presentation genes. CD8+ cytotoxic T and mature natural killer cells showed epigenetic preactivation of effector function. Intercellular communication analysis revealed that regular exercise enhanced major histocompatibility complex-I/II signaling between APCs and T cells and suppressed inflammatory networks. Together, these findings elucidate molecular mechanisms underlying the health benefits of regular exercise and offer a theoretical basis for enhancing public health and preventing chronic diseases.