Hongyan Fan

Cardiovascular–kidney–metabolic (CKM) syndrome represents a pathophysiological continuum linking metabolic dysfunction, chronic kidney disease (CKD), and cardiovascular disease (CVD) through shared mechanisms, including insulin resistance, chronic inflammation, endothelial dysfunction, mitochondrial impairment, and maladaptive interorgan crosstalk. Although exerkines have emerged as key mediators of exercise-induced benefits, an integrated exerkine-centered framework spanning the CKM spectrum remains lacking. This review synthesizes current evidence on the multiorgan origins and biological roles of major exerkines, including myokines, adipokines, hepatokines, cardiokines, osteokines, lipid mediators, and extracellular vesicle–associated cargos. Moreover, extending beyond reductionist descriptions, we propose a higher-level mechanistic synthesis in which exerkines function as coordinated “signatures” across CKM phenotypes, converging on key regulatory hubs, particularly AMP-activated protein kinase (AMPK)–peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-mediated metabolic adaptation and the Klotho/fibroblast growth factor (FGF) axis that links renal, metabolic, and cardiovascular regulation. From a translational perspective, adiponectin, FGF21, apelin, and Klotho demonstrate the most consistent associations with cardiometabolic and renal outcomes in humans. However, clinical application remains constrained by uncertain causality, context-dependent resistance, and variability in assay performance. Overall, exerkines are best conceptualized as components of an integrated signaling network rather than isolated therapeutic targets. Meanwhile, future progress will depend on defining disease-stage-specific exerkine signatures and establishing associated causal relevance in humans.

Heart failure with preserved ejection fraction (HFpEF) is rapidly emerging as a predominant form of heart failure worldwide. Its pathogenesis extends beyond traditional hemodynamic abnormalities and involves multiple pathways, such as systemic metabolism, inflammation, and endothelial dysfunction. Type 2 diabetes mellitus (T2DM), which is present in up to 45% of patients with HFpEF, is one of the most common and clinically important comorbidities of HFpEF. T2DM not only significantly increases its incidence but also leads to more severe complications and poorer prognosis, constituting a distinct clinical phenotype known as "diabetic HFpEF.” In recent years, the role of the gut microbiota (GMB) as a central hub linking metabolism and the cardiovascular system has become increasingly prominent. This review summarizes the epidemiological and pathophysiological connections between T2DM and HFpEF, with a focus on characteristic alterations in gut dysbiosis in patients with diabetic HFpEF and the underlying mechanisms involving microbiota-derived metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and bile acids (BAs). It also discusses how the cardiovascular protective effects of novel antidiabetic drugs are closely related to their potential mechanisms of modulating gut microbiota ecology and restoring metabolic balance. However, current evidence remains largely mechanistic and observational, and the causal relationships between gut dysbiosis and diabetic HFpEF require further validation. Overall, GMB represents an important and modifiable target in patients with diabetic HFpEF, offering new directions for both mechanistic research and therapeutic interventions.

Heart failure with preserved ejection fraction (HFpEF) has emerged as the predominantform of heart failure (HF) worldwide and is increasingly recognized as a systemic syndrome closely linked to metabolic dysfunction. Furthermore, metabolic dysfunction–associated steatotic liver disease (MASLD), a highly prevalent yet often underrecognized comorbidity in patients with HFpEF, has attracted increasing attention. Accumulating epidemiological evidence demonstrates a significant association between MASLD and HFpEF, suggesting shared pathophysiological foundations that extend beyond coincidental coexistence. Mechanistically, MASLD contributes to the development and progression of HFpEF through a network of interconnected pathways, including chronic low-grade inflammation, insulin resistance (IR), dysregulated lipid metabolism, endothelial dysfunction, the gut–liver–heart axis, and as liver-derived mediators that influence cardiac structure and function. These overlapping mechanisms underlie the pronounced clinical and phenotypic heterogeneity of HFpEF and may help explain the limited efficacy of conventional heart failure therapies. This review summarizes current diagnostic and therapeutic strategies for HFpEF and MASLD and proposes an integrated, multiorgan framework to improve clinical recognition and management. A deeper understanding of liver–heart interactions is essential to redefining cardiometabolic disease, shifting from an organ-centric perspective toward a more integrated, mechanism-based approach.

The global prevalence of obesity is rapidly in creasing, significantly increasing the incidence of heart failure with preserved ejection fraction (HFpEF). Obesity, one of the most common clinical phenotypes of HFpEF, facilitates the onset and progression of HFpEF via multiple pathophysiological mechanisms. Lifestyle intervention, which serves as the cornerstone of weight loss, plays a crucial role in the management of HFpEF. Novel antidiabetic therapies, including sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and glucose‒dependent insulinotropic polypeptide (GIP)/glucagon‒like peptide-1 (GLP-1) dual receptor agonists, have favourable effects on clinical outcomes in obese HFpEF patients. For patients with heart failure (HF) prior to bariatric surgery (BSx), there is moderate evidence supporting the efficacy and safety of the procedure. This review systematically summarizes the clinical evidence related to metabolic therapy treatment strategies for obese HFpEF patients and discusses the potential advantages of such therapy.