Ziziphus lotus has traditionally been used as a phytotherapeutic agent for cardiovascular, metabolic, immune, nervous, and reproductive health. In this study, a multidisciplinary approach combining in vivo nutrigenomic analyses, cardiovascular physiology experiments, and phytochemical and ethnobotanical data was employed to investigate the effects of aqueous Z. lotus extract (ZLex). ZLex significantly upregulated genes involved in nitric oxide synthesis (Camk1, Gch1), smooth muscle relaxation, and angiotensin degradation, correlating with reductions in systolic, diastolic, and mean arterial blood pressure. In addition, ZLex modulated key neurotransmission-related genes (Dbh, Htr2a, Gabrg3), supporting its potential anxiolytic and neuroprotective actions. Immune modulation was indicated by the upregulation of genes associated with anti-inflammatory and antimicrobial responses. Metabolic benefits were linked to the regulation of genes involved in glucose and lipid metabolism, mitochondrial function, and body weight control. Positive effects on reproductive health were suggested by the induction of genes implicated in spermatogenesis. These effects are likely mediated by bioactive constituents such as rutin, kaempferol-3-O-rutinoside, 3′,5′-di-C-β-glucopyranosylphloretin, a quercetin dirhamnosyl-galactoside, and myricetin-3-O-rutinoside. Altogether, the findings provide mechanistic support for the traditional use of Z. lotus and highlight its therapeutic potential in managing hypertension and other chronic disorders, including diabetes, obesity, and anxiety.
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