Essential Pharmacokinetics and Pharmacodynamics of Naringenin: Underpinning the Cardioprotective Potential of Citrus‐Based Traditional Medicine

ABSTRACT Naringenin, a naturally occurring flavanone predominantly found in citrus fruits, exhibits diverse biological activities, including antioxidant, antitumor, anti‐inflammatory, anti‐adipogenic, and cardioprotective effects. Current literature has largely emphasized naringin, the glycosylated derivative of naringenin. However, as naringenin represents the physiologically active form, it is critical to consolidate and evaluate existing knowledge on its mechanisms of action, particularly in relation to cardiovascular disease (CVD). In this review, we examine the effects of naringenin on CVD and the major hub pathways underlying its pleiotropic effects. Naringenin demonstrates benefecial effects on multiple risk factors of CVD such as diabetes, dyslipidemia, ischemia, smoking and obesity through diverse signaling pathways. Notably, naringenin regulates the cyclic guanosine monophosphate (cGMP)‐protein kinase G (PKG) hub pathway, thereby influencing a spectrum of downstream cascades contributing to its therapeutic potential. Despite these promising findings, the major drawback in the effect of naringenin is its limited bioavailability. Naringenin occurs in glycosylated forms (naringin, narirutin, and naringenin‐glucoside) and as aglycones (naringenin) with both the forms exhibiting cardioprotective properties. However, with only limited number of clinical trials have investigated its efficacy in CVD, further clinical trials are essential to establish its naringenin's therapeutic value as a potential drug candidate.