Endoplasmic Reticulum Stress: A Novel Target for the Prevention and Treatment of Hypertension and Its Related Diseases

Endoplasmic reticulum stress (ERS) emerges as a critical pathophysiological nexus in hypertension and related cardiovascular diseases. Chronic ERS activation via the IRE1α‐XBP1, ATF6, and PERK pathways drives vascular endothelial dysfunction (reduced NO bioavailability, increased ET‐1), renin‐angiotensin system (RAS) hyperactivation, sympathetic overactivation, and vascular smooth muscle cell (VSMC) maladaptive proliferation/apoptosis, collectively promoting hypertension progression and end‐organ damage. Pharmacological targeting of ERS demonstrates therapeutic promise: chemical chaperones 4‐phenylbutyric acid (4‐PBA) and tauroursodeoxycholic acid (TUDCA) stabilise proteostasis, reduce oxidative stress, and inhibit apoptosis; antioxidants N‐acetylcysteine (NAC) and melatonin attenuate ERS‐oxidative stress crosstalk. Notably, conventional antihypertensives—ACE inhibitors and angiotensin receptor blockers (ARBs)—exert ancillary benefits by suppressing ERS beyond their primary RAS blockade. Preclinical evidence supports the efficacy of these strategies in reversing hypertensive pathophysiology. Future research must prioritise isoform‐selective ERS modulator development, validation in human trials, biomarker discovery, and elucidating ERS roles in therapy‐induced hypertension. Targeting ERS represents a transformative mechanotherapeutic paradigm for precision hypertension management.