Renin Inhibition and eNOS Upregulation as Novel Mechanisms of Antihypertensive Food Peptides

ABSTRACT Food‐derived bioactive peptides are gaining significant attention as safer, natural alternatives to synthetic drugs for managing hypertension. While research has predominantly focused on angiotensin‐converting enzyme (ACE) inhibition, the frequent disconnect between in vitro potency and in vivo efficacy suggests the involvement of alternative molecular mechanisms. This review critically assesses recent literature regarding two pivotal non‐ACE inhibitory pathways: the inhibition of renin, the rate‐limiting enzyme of the renin‐angiotensin system (RAS), and the upregulation of endothelial nitric oxide synthase (eNOS). We examine insights from studies characterizing peptides acting through these pathways and discuss emerging mechanisms such as angiotensin II receptor blockade and the ACE2/Ang(1‐7)/MasR axis. Furthermore, we identify critical knowledge gaps arising from methodological inconsistencies in in vivo assays and the limited number of in vivo validation studies. The evidence suggests that antihypertensive food peptides function through multifaceted mechanisms, offering a holistic approach to blood pressure regulation. Future research must prioritize integrated approaches combining in silico , in vivo, and in vivo models to bridge existing translational gaps.