Molecular mechanisms of aberrant fatty acids metabolism in driving cardiovascular diseases: key regulatory targets and dietary interventions

Abstract

In recent years, cardiovascular diseases (CVDs) have emerged as one of the leading global risk factors for mortality. As the primary energy source for myocardial metabolism, alterations in fatty acid (FAs) metabolism play a crucial role in myocardial energy imbalance in patients with CVDs. These metabolic disruptions can affect vascular and myocardial cell function through various mechanisms, thereby contributing to the onset and progression of CVDs. Additionally, FAs are abundant in the daily diet, further emphasizing the importance of regulating FA metabolism as a potential therapeutic and preventive strategy for CVDs and its risk factors. This review systematically examines the relationship between the metabolism of short-chain, medium-chain, and long-chain FAs and CVDs, including atherosclerosis (AS), coronary heart disease (CHD), hypertension, arrhythmia, cardiomyopathy, and heart failure (HF). It also delves into the underlying mechanisms by which these FAs influence CVD pathology. Evidence suggests that short-chain FAs (SCFAs) inhibit inflammation, reduce oxidative stress, and improve endothelial function through the activation of GPR41/43 receptors. ω-3 polyunsaturated FAs (ω-3 PUFAs) reduce CVD risk by modulating lipid metabolism, inhibiting platelet aggregation, and exerting anti-inflammatory effects, whereas ω-6 PUFAs may exacerbate disease progression due to their pro-inflammatory properties. Saturated FAs (SFAs) promote CVDs by inducing lipotoxicity, oxidative stress, and vascular remodeling. Furthermore, the imbalance of key molecules in FA metabolism, such as CD36, CPT1, PPARs, and AMPK, is closely linked to myocardial energy dysfunction, inflammation, and fibrosis. This review highlights the potential of dietary interventions—such as increased intake of ω-3 PUFAs and SCFAs—as well as the targeting of FA metabolic pathways (e.g., FFARs, AMPK activators) in the prevention and treatment of CVDs. It also emphasizes the need for further clinical studies to verify the efficacy and mechanisms of these approaches. Overall, this review provides a comprehensive theoretical framework for understanding the role of FAs metabolism in CVDs and outlines directions for developing novel therapeutic strategies.