The Role of the Pentose Phosphate Pathway in Cardiovascular Diseases

Cardiovascular diseases (CVDs) are the leading contributors to global mortality, characterized by multifactorial etiology involving diverse cell types such as cardiomyocytes and immune cells. Metabolic reprogramming in cardiomyocytes and immune cells is involved in the pathophysiology of CVDs, and the pentose phosphate pathway (PPP) plays a critical role. The PPP mainly generates nicotinamide adenine dinucleotide phosphate (NADPH) and ribose-5-phosphate (R5P). NADPH not only maintains cellular antioxidant capacity by regenerating reduced glutathione (GSH) and thioredoxin (Trx) but also participates in reactive oxygen species (ROS) production through NADPH oxidases (NOX) under specific conditions, thus exerting dual roles in cardioprotection and oxidative damage. Meanwhile, R5P contributes to nucleotide biosynthesis, supporting cell cycle progression and immune cell expansion. Therefore, PPP is necessary for cellular proliferation and function. In cardiomyocytes, enhanced PPP reduces oxidative stress and facilitates myocardial repair. The PPP modulates phenotypes and functions in immune cells and is involved in inflammatory responses and tissue repair. Therapeutic interventions targeting key enzymes of the PPP, like glucose-6-phosphate dehydrogenase (G6PDH), can alleviate oxidative damage, reduce pathological fibrosis, and modulate immune cell activity in CVDs. Some inhibitors of G6PDH, such as dehydroepiandrosterone and 6-amino-nicotinamide (6-AN), are in the preclinical stage. This review emphasizes the importance of the PPP in CVDs, advocating for targeted metabolic therapies to enhance treatment efficacy and patient outcomes in CVDs.