Key Takeaways & Executive Findings
- •• Metabolic reprogramming is a central mechanism driving the initiation and progression of cardiometabolic syndrome, beyond traditional hormonal and hemodynamic factors. • Multiomics platforms (genomics, proteomics, metabolomics, metagenomics) are pivotal for identifying novel biomarkers and therapeutic targets in CMS. • Obesity-induced adipose tissue dysfunction, inflammation, and ectopic lipid accumulation are key triggers of metabolic reprogramming and CMS pathophysiology. • Restoring metabolic flexibility through pharmacological interventions represents a promising therapeutic strategy to halt CMS progression.
Abstract
Cardiometabolic syndrome (CMS), a combination of central obesity, insulin resistance, dyslipidemia, and hypertension, accounts for a significant portion of the global incidence of type 2 diabetes and cardiovascular disease. Traditionally, hormonal and hemodynamic dysregulation have been considered the primary causes of CMS. However, increasing evidence shows that metabolic reprogramming, which involves long-lasting, tissue-specific changes in cellular metabolism, is a common cause of the initiation and progression of CMS. This review examines the systemic metabolic alterations, the molecular pathways facilitating these modifications, and the transformative impact of multiomics platforms on the discovery of novel biomarkers and therapeutic targets. We also discuss drugs that can help restore metabolic flexibility and stop disease progression.
1. Introduction
Cardiometabolic syndrome (CMS) encompasses the coexistence of metabolic disorders such as central obesity, insulin resistance (IR), dyslipidemia, and hypertension [1,2]. The heterogeneity and asymptomatic nature of CMS permanently worsen health and, over a long period, lead to the development of cardiometabolic diseases (CMDs) [3]. CMS accounts for a significant proportion of the global incidence of type 2 diabetes (T2D) and cardiovascular disease (CVD) [4,5]. In addition, CMS is associated with the development of other CMDs, such as nonalcoholic fatty liver disease, chronic kidney disease, and stroke [6–8]. Therefore, numerous investigations are aimed at discovering the molecular mechanisms of CMS and identifying a reliable biomarker for early detection and effective therapy.
The combination of low physical activity, unhealthy diet, excess body mass, and daily stress is a risk factor for an increased incidence of CMS. Central or abdominal obesity may be regarded as the root cause of CMS, since obesity is often accompanied by the development of IR, dyslipidemia, and hypertension [9,10]. Obesity often causes low-grade inflammation, leading to the recruitment of various factors that induce obesity-related cardiometabolic complications [11]. Additionally, obesity affects the normal functioning of the cardiovascular system (CVS), leading to hypertension and an increased workload on the heart [3]. IR is characterized by hyperglycemia, altered metabolism of free fatty acids (FFAs), and increased oxidative stress (OS) [3]. Another CMS factor, hypertension, directly affects the CVS by changing the structure and function of the heart and blood vessels [12]. Dyslipidemia, characterized by elevated blood lipid levels, is a critical factor in endothelial dysfunction and the progression of plaque formation [13,14].
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Milan Obradovic, Jelena Radovanovic, Julijana Stanimirovic, Bozidarka Zaric, Esma R. Isenovic (2026). Metabolic Reprogramming in Cardiometabolic Syndrome: Mechanisms, Biomarkers, and Therapeutic Approaches. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025255
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Frequently Asked Questions
What is cardiometabolic syndrome (CMS)?
Cardiometabolic syndrome is a cluster of metabolic disorders including central obesity, insulin resistance, dyslipidemia, and hypertension, which collectively increase the risk of type 2 diabetes and cardiovascular disease.
How does metabolic reprogramming contribute to CMS?
Metabolic reprogramming involves long-lasting, tissue-specific changes in cellular metabolism that drive the initiation and progression of CMS, often triggered by obesity and associated inflammation.
What role do multiomics platforms play in CMS research?
Multiomics platforms (genomics, proteomics, metabolomics, metagenomics) enable comprehensive profiling of molecular alterations, facilitating the discovery of novel biomarkers and therapeutic targets for CMS.
What are potential therapeutic strategies for CMS?
Therapeutic strategies aim to restore metabolic flexibility, reduce inflammation, and improve insulin sensitivity, using drugs that target metabolic pathways and lifestyle interventions.
Why is obesity considered a root cause of CMS?
Obesity, especially visceral adiposity, leads to adipose tissue dysfunction, excessive free fatty acid release, inflammation, and ectopic lipid accumulation, which promote insulin resistance, dyslipidemia, and hypertension.
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