Metabolomics and Precision Medicine in Resistant Hypertension: Pathophysiological Insights, Biomarker Discovery, and Translational Strategies.

Resistant hypertension (RH), defined as uncontrolled blood pressure despite the use of at least three optimally dosed antihypertensive agents, including a diuretic, remains a major clinical challenge associated with elevated cardiovascular risk. Metabolomics offers a dynamic approach to characterize biochemical perturbations related to amino acid metabolism, lipid remodeling, mitochondrial dysfunction, oxidative stress, renal impairment, and gut microbiota-derived metabolites. However, current evidence remains limited by small sample sizes, cross-sectional designs, heterogeneous definitions of RH, inadequate exclusion of pseudoresistance, medication confounding, and limited external validation. This structured narrative review synthesizes RH-specific metabolomic evidence and distinguishes it from findings extrapolated from broader hypertension populations. We further discuss methodological challenges, replication gaps, pharmacometabolomic confounding, and validation standards required for clinical implementation. Integrating metabolomics with clinical phenotyping, genomics, proteomics, and microbiome profiling may eventually support RH phenotyping, treatment-response prediction, and biomarker-guided precision medicine, but large longitudinal cohorts with confirmed true RH are needed before clinical translation.