Epigenetic mechanisms of salt-sensitive hypertension

Salt-sensitive hypertension (SSH) is a complex and heterogeneous phenotype characterized by an abnormal blood pressure response to dietary salt intake. While genetic factors have been extensively explored, emerging evidence highlights the pivotal role of epigenetic mechanisms (DNA methylation, histone modifications and non-coding RNAs) in modulating gene expression without altering the DNA sequence. These modifications respond dynamically to environmental stimuli such as diet, aging, stress and prenatal conditions, contributing to both the development and progression of SSH. This review summarizes current knowledge on the epigenetic regulation of genes involved in sodium handling, vascular tone and inflammation, focusing on pathways such as the renin–angiotensin–aldosterone system, the Klotho–Wnt5a–RhoA axis and the influence of the intrauterine environment. Special attention is given to transgenerational epigenetic inheritance and aging-related changes, as well as the reversibility of some epigenetic marks through lifestyle interventions such as salt restriction and physical activity. Understanding the interplay between environmental exposures and epigenetic regulation offers a new frontier for precision medicine in hypertension, but despite the promising findings, SSH-specific human data remain limited and a unifying epigenetic signature distinguishing SSH from other hypertensive phenotypes has yet to be defined. Further longitudinal studies and biomarker discovery efforts are needed to translate these insights into personalized preventive and therapeutic strategies.