Search Results (1,300)

Background/Objectives: Obstructive sleep apnea (OSA) causes recurrent apneas/hypopneas and intermittent oxygen desaturation during sleep. Chronic intermittent hypoxia (CIH) may be linked to metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis through metabolic dysfunction. This study evaluated the relationship between OSA severity/hypoxemia indices and MASLD and fibrosis assessed by transient elastography. Methods: We prospectively enrolled 400 adults evaluated for suspected OSA at a respiratory disease outpatient clinic in Rize, Türkiye. All patients underwent overnight polysomnography. The apnea–hypopnea index (AHI), oxygen desaturation index (ODI), mean SpO₂, and mean of each participant’s minimum SpO₂ values were recorded. MASLD and fibrosis were assessed in the same individuals using FibroScan, with CAP (controlled attenuation parameter) and LSM (liver stiffness measurement) values recorded. OSA severity was categorized by AHI, and multivariable logistic regression was used to identify independent associations. Results: MASLD was present in 76% and fibrosis in 34.5% of patients. Patients with fibrosis had higher AHI (13.8 [8.2–35.2]) and ODI (11.5 [4.5–33.2]) and lower minimum SpO₂ (p < 0.001). In multivariable models, BMI (OR 1.09; p < 0.001) and metabolic syndrome (OR 3.34; p < 0.001) were independently associated with MASLD, while BMI (OR 1.02; p < 0.001), metabolic syndrome (OR 2.03; p = 0.015), and ALT (OR 1.02; p = 0.032) were independently associated with fibrosis. Conclusions: MASLD and fibrosis were associated with OSA severity and hypoxemia before multivariable adjustment. However, after adjustment for obesity-related factors, liver outcomes were primarily explained by BMI and metabolic syndrome. Liver assessment should be considered in patients with OSA, particularly in those with high BMI and metabolic syndrome. Full article

Objective: Alzheimer’s disease (AD) is traditionally characterized by amyloid-β and tau pathology; however, accumulating evidence indicates that metabolic and inflammatory dysfunctions are early, central contributors to disease development. This narrative review explores how metabolic disturbances influence AD pathophysiology. Methods: A comprehensive literature search was performed on PubMed, Embase, and Scopus. Selected studies were original studies or reviews published in English within the past five years involving human subjects. Case reports, case series, editorials, and non-human studies were excluded. A total of 64 articles were reviewed and summarized. Results: Cerebral glucose hypometabolism, mitochondrial impairment, insulin resistance, oxidative stress, and neuroinflammation were observed throughout the AD spectrum. These metabolic changes often appeared before significant amyloid accumulation and were more closely linked to tau pathology and cognitive decline. Early microglial activation was linked to transient glucose hypermetabolism, progressing to glucose hypometabolism and neurodegeneration as the disease advanced. Conclusions: AD is associated with a gradual breakdown of metabolic and inflammatory homeostasis, which occurs before and promotes the development of traditional neuropathological features. Addressing early metabolic vulnerabilities may be essential for effective disease intervention and prevention. Full article

Preeclampsia (PE) has traditionally been regarded as a pregnancy-limited hypertensive disorder; however, accumulating evidence increasingly positions it as a pivotal early-life vascular stress test that manifests underlying vulnerabilities and accelerates biological aging. Women with a history of PE exhibit a heightened susceptibility to premature-onset multi-systemic diseases, specifically cardiovascular, ovarian, renal, and metabolic decline. This suggests that PE acts as a catalyst for accelerated aging, driven by shared pathophysiological pathways that represent common mechanisms of systemic senescence. This review provides a comprehensive analysis of the epidemiological links and pathogenic drivers underpinning accelerated systemic aging following PE, with a specific focus on the cardiovascular-ovarian axis. Epidemiological data consistently demonstrate that women with prior PE exhibit significantly reduced anti-Müllerian hormone (AMH) levels, translating to an estimated 1.5-year acceleration in reproductive aging. In parallel, PE is associated with a twofold increase in lifetime cardiovascular disease (CVD) risk and the onset of chronic hypertension occurring an average of 7.7 years earlier. However, reconciling the phenotypic heterogeneity of PE and transcending the constraints of non-experimental designs are essential for firmly establishing this accelerated aging paradigm. At the molecular level, PE and ovarian aging converge on shared pathways—including mitochondrial dysfunction, oxidative stress, inflammation, and epigenetic dysregulation—collectively defining a distinct pathogenic ovarian–vascular aging axis. Proposed geroscience-based strategies advocate for refined risk stratification by incorporating molecular aging biomarkers—such as epigenetic clocks and inflammatory profiles—alongside conventional clinical indicators. This integrative framework facilitates the early identification of high-risk aging phenotypes, enabling targeted monitoring and timely interventions to preemptively modulate accelerated aging pathways. Pharmacological approaches within this framework emphasize the judicious repurposing of established agents, such as metformin, statins, and SGLT2 inhibitors, while emerging gerotherapeutics, including senolytics and senomorphics, provide a conceptual foundation for targeting the fundamental biological drivers of senescence. Although these geroprotective strategies, including the repurposing of established agents and the use of senolytics, offer innovative conceptual frameworks for targeting the fundamental drivers of senescence, they remain largely exploratory and require further clinical validation. Such strategies offer novel opportunities to shift the clinical focus from treating isolated comorbidities to modulating the shared molecular substrates of aging, ultimately promoting healthy aging and functional longevity in the elderly female population. Full article

Type 2 diabetes mellitus (T2DM) and obesity affect hundreds of millions of adults worldwide and represent leading drivers of cardiovascular disease, chronic kidney disease, and escalating healthcare expenditures. Incretin-based therapies have fundamentally reshaped cardiometabolic disease management, with dual- and triple-receptor agonists extending the benefits of traditional glucagon-like peptide-1 (GLP-1) receptor agonism. By synthesizing clinical, mechanistic, and real-world data, this review examines the evolving therapeutic landscape of GLP-1-based multi-agonists. Dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists demonstrate superior metabolic efficacy compared with GLP-1 receptor agonists alone, achieving greater reductions in body weight and glycemic indices across diverse patient populations. Emerging triple agonists targeting GLP-1, GIP, and glucagon receptors further enhance metabolic outcomes, with weight loss approaching that observed following bariatric surgery in late-phase clinical trials. Mechanistically, multi-receptor co- agonism produces synergistic effects through complementary pathways, including appetite suppression, glucose-dependent insulin secretion, improved adipose tissue metabolism, increased energy expenditure, enhanced hepatic lipid oxidation, and reductions in hepatic steatosis. Beyond glycemic and weight endpoints, GLP-1-based therapies confer clinically meaningful cardiovascular and renal protection. Trials consistently demonstrate reductions in major adverse cardiovascular events across populations with and without T2DM, while kidney-specific trials show significant slowing of disease progression. However, gastrointestinal adverse events remain common and contribute to substantial treatment discontinuation, particularly in real-world settings. Despite their transformative efficacy, the population-level impact of these therapies is constrained by significant implementation barriers, including high drug costs, limited insurance coverage, restrictive utilization management policies, and pronounced racial and socioeconomic disparities in access. Emerging innovations including oral formulations, longer-acting injectables, and novel peptide combinations look to improve tolerability, adherence, and scalability, while therapeutic indications continue to expand to conditions such as metabolic dysfunction-associated steatohepatitis, chronic kidney disease, obstructive sleep apnea, and neurodegenerative disease. This review provides a comprehensive framework for understanding the clinical potential, mechanistic basis, and real-world challenges of GLP-1-based multi-agonists and outlines key priorities for optimizing implementation and maximizing their impact on global cardiometabolic health. Full article

The autonomic nervous system (ANS) plays a key role in cardiovascular regulation by maintaining hemodynamic and metabolic homeostasis through balanced sympathetic and parasympathetic activity. While autonomic dysfunction is classically associated with diabetes, neurodegenerative diseases, autoimmune neuropathies, and chronic cardiovascular conditions, growing evidence suggests that disturbances in iron metabolism represent an underrecognized contributor to cardiac autonomic dysregulation. This narrative review summarizes data from 107 studies on ANS disorders, including 49 investigating cardiovascular involvement. Reported abnormalities included reduced heart rate variability and baroreflex sensitivity, prolonged P-wave duration and QT dispersion, and deviations in non-invasive autonomic testing parameters. In iron overload states, these changes appear to be driven primarily by oxidative stress, whereas in iron deficiency they are likely mediated by tissue hypoxia. Importantly, several studies indicate that normalization of iron homeostasis may partially reverse autonomic dysfunction. This potentially reversible component underscores the clinical relevance of screening for and correcting iron imbalance not only to improve hematological status but also to reduce cardiovascular risk. Large-scale, multicenter studies using standardized autonomic assessment protocols are required to clarify prognostic implications and inform evidence-based clinical guidelines. Full article

Background and Clinical Significance: Over the last two decades, glucagon-like peptide-1 (GLP-1) receptor agonists have dramatically improved the management of type 2 diabetes mellitus and obesity. Currently, little is known about the use of semaglutide (a second-generation GLP-1 receptor agonist) in patients with X chromosome abnormalities. Herein, we describe the therapeutic use of semaglutide in a woman with a partial deletion of the X chromosome long arm (partial Xq deletion) and comorbid obesity. We also conducted a narrative mini-review on overweight, obesity and common metabolic derangements in patients with partial Xq deletions and Turner syndrome. Case Presentation: A 65-year-old Italian woman with a partial Xq deletion, class 1 obesity, insulin resistance, prediabetes, hypercholesterolemia and metabolic dysfunction-associated steatotic liver disease (MASLD) was referred to our Institution for persistent difficulty in managing excess body weight despite regular adherence to different structured physical activity programs and hypocaloric diets. Therefore, we prescribed a combination therapy based on low-dose metformin (500 mg/day) and once-weekly subcutaneous semaglutide (as an adjunct to lifestyle intervention). At 5 months after initiation of the combination therapy, blood tests showed metabolic improvements, including improvement of prediabetes (0.3-percentage-point reduction in glycated hemoglobin [HbA1c] values) and normalization of markers of insulin sensitivity and insulin resistance (QUICKI, HOMA-IR and TyG index). At 8 months, the patient showed substantial weight loss, which amounted to 13.8 kg (percent total body weight loss: 20.95%), and was accompanied by a notable reduction in waist circumference (−14.1 cm). Moreover, body mass index (BMI)-based weight status improved from class 1 obesity to overweight: BMI value of 25.1 kg/m² at 8 months vs. 31.8 kg/m² at baseline (near-normalization of BMI values). Bioelectrical impedance analysis (BIA) revealed that the patient’s overall weight loss consisted of 74.6% fat mass (FM) loss (−10.3 kg) and 25.4% fat-free mass (FFM) loss (−3.5 kg). Despite the expected FFM reduction in absolute terms, percent FFM increased at 8 months (+9.6%). This increase in percent FFM was accompanied by a reduction in percent FM at 8 months (−9.6%), indicating an overall improvement in body composition. Normalization of percent FM and FFM values (28.6% and 71.4%, respectively) was also achieved at 8 months. These body composition changes are in line with those observed in clinical trials investigating the use of semaglutide in patients with overweight or obesity. At 6 months, an abdominal ultrasound also showed the disappearance of the sonographic characteristics suggestive of mild-to-moderate hepatic steatosis. Low-dose metformin (500 mg/day) and subcutaneous semaglutide (up to a weekly dose of 1.7 mg) were well tolerated by the patient. Conclusions: To the best of our knowledge, this is the first case documenting the effective use of once-weekly subcutaneous semaglutide plus low-dose metformin combination therapy for the treatment of obesity and prediabetes in a woman with a partial Xq deletion. Large prospective cohort studies are warranted to better investigate the safety and efficacy profile of semaglutide (alone or in combination with metformin) in patients with numerical and structural X chromosome abnormalities, comorbid overweight/obesity and related metabolic disorders. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its consequences represent a growing global health burden that urgently requires physiologically relevant in vitro models beyond conventional 2D culture systems. In this study, we report the successful establishment of 45 patient-derived liver organoid lines. These organoids were generated from healthy, steatotic and cirrhotic tissues collected from 207 liver surgeries at RWTH University Hospital Aachen, with an initiation success rate of 82%. The organoids were propagated for at least six passages using an optimized protocol. Multiplex immunofluorescence analysis revealed highly proliferative structures with approximately 40% Ki-67-positive cells expressing hepatocyte (Albumin and HNF4α) and cholangiocyte (CK19) markers. Intermittent LGR5 staining suggested the presence of liver progenitor cell features. Quantitative PCR results confirmed variable HNF4α expression, indicating inter-patient heterogeneity in differentiation status. Time-lapse imaging combined with mathematical modeling uncovered a biphasic growth dynamic with an initial linear expansion in the first 15 h, followed by exponential growth (doubling time ≈ 20.6 h) between 30 and 72 h. Overall, our workflow produced genetically and phenotypically stable liver organoids that recapitulate essential features of various hepatic conditions. This provides a solid foundation for disease modeling, potential drug testing, and quantitative systems biology. Full article

Background/Objectives: This study aimed to evaluate the predictive value of the triglyceride-glucose index with body mass index (TyG-BMI) and the triglyceride-to-high-density lipoprotein-cholesterol (TG/HDL-C) ratio for predicting the occurrence of metabolic dysfunction-associated steatotic liver disease (MASLD) in obstructive sleep apnea (OSA). Methods: Data from patients diagnosed with OSA were analyzed in this retrospective cohort study. The participants were stratified into two groups: OSA alone and OSA with MASLD. The clinical characteristics and polysomnography data were collected. TyG-BMI and TG/HDL-C ratios were categorized into tertiles. Logistic regression and receiver operating characteristic (ROC) curve analyses were conducted to identify risk factors and assess their predictive performance for MASLD in OSA. Results: Among the 133 patients with OSA, 104 (78.2%) were diagnosed with MASLD. Multivariate analysis identified alanine aminotransferase (ALT), alkaline phosphatase, and TyG-BMI as independent risk factors for MASLD development in patients with OSA. Both TyG-BMI and TG/HDL-C ratio were significant predictors of MASLD in this patient population. The optimal cut-off values for TyG-BMI and TG/HDL-C ratio were 0.546 (sensitivity, 79.6%; specificity, 75.0%) and 0.539 (sensitivity, 93.2%; specificity, 60.7%), respectively. Combining TyG-BMI with ALT improved the predictive accuracy, yielding a cutoff of 0.696 (sensitivity, 76.7%; specificity, 92.9%). Similarly, the combination of TG/HDL-C ratio with ALT resulted in a cutoff value of 0.728 (sensitivity, 83.5%; specificity, 89.3%). Conclusions: TyG-BMI and the TG/HDL-C ratio are effective predictors of MASLD in patients with OSA. A combined model incorporating these indices with ALT levels demonstrated enhanced predictive accuracy for MASLD in this population. These indices are well-suited for risk stratification in resource-constrained settings facing a rising dual burden of OSA and MASLD. Full article

Background: Coronary slow flow (CSF) is a microvascular disorder characterized by delayed perfusion despite the absence of significant epicardial stenosis. Although its exact pathophysiology remains unclear, endothelial dysfunction, oxidative stress, and atherogenic dyslipidemia have been implicated. Traditional lipid parameters may not fully capture the atherogenic burden, whereas atherogenic indices such as the atherogenic index of plasma (AIP), atherogenic coefficient (AC), and Castelli risk indices (CRI-I and CRI-II) may provide better predictive value. This study aimed to investigate the association between atherogenic indices and CSF in a large real-world angiographic cohort. Methods: This retrospective study included 25,486 patients who underwent coronary angiography between September 2020 and June 2024. A total of 464 patients with CSF (diagnosed by TIMI frame count criteria) and 408 controls with normal coronary flow (NCF) were identified. Atherogenic indices, including AIP, AC, CRI-I, CRI-II, and non-HDL cholesterol (non-HDL-C), were calculated. Multivariate logistic regression analysis identified independent predictors of CSF, while receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of each lipid-related parameter. Results: Patients with CSF had significantly higher AIP, AC, non-HDL-C, and CRI indices and lower HDL-C levels compared to controls (all, p < 0.05). Multivariate analysis identified AIP (OR: 1.73, 95% CI: 1.18–2.44, p = 0.004), age (OR: 1.02, 95% CI: 1.01–1.06, p = 0.014) and smoking (OR: 2.22, 95% CI: 1.36–2.84, p = 0.003) as independent predictors of CSF. ROC analysis showed modest but statistically significant discriminatory capacity for AIP (cut-off: 0.50; AUC: 0.629; 95% CI: 0.591–0.667; p < 0.001). AIP also demonstrated a weak yet significant correlation with mean TIMI frame count (rho = 0.245, p < 0.001), suggesting a potential link to microvascular dysfunction. Conclusions: Among the evaluated atherogenic indices, only AIP demonstrated an independent association with CSF. Despite modest discriminative performance that does not support standalone clinical prediction, AIP may reflect an underlying metabolic phenotype associated with CSF and serve as a complementary marker alongside traditional risk assessment. These findings should be interpreted as hypothesis-generating and warrant prospective validation. Full article

Background: Post-COVID-19 cognitive impairment, commonly referred to as “brain fog,” represents a significant clinical problem, yet its underlying mechanisms remain incompletely understood. New research indicates that long-term cognitive consequences of SARS-CoV-2 infection may result from chronic immunological dysregulation and neurometabolic changes. Objective: We aimed to assess the associations between cognitive performance, cerebral glucose metabolism, and inflammatory markers in patients with COVID-19 brain fog symptoms. Methods: This study included 47 patients with post-COVID-19 cognitive complaints enrolled in the COVMENT trial. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). Brain glucose metabolism was evaluated with FDG PET-CT, and inflammatory markers, including C-reactive protein (CRP), monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, eosinophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR), were measured. Correlation analyses, logistic regression, and ROC analysis were performed to explore relationships between these factors. Results: A lower score of the MoCA abstraction domain correlated significantly with lower FDG uptake in multiple brain regions, including inferior parietal lobules and precuneus. Among inflammatory markers, only PLR demonstrated significant associations with both brain metabolism and abstraction performance. Lower PLR values were associated with greater neurometabolic impairment, and PLR < 130.1 was associated with abnormal abstraction performance. Conclusions: Post-COVID-19 cognitive dysfunction can be associated with selective neurometabolic alterations in brain regions supporting abstract reasoning. PLR seems to be associated with both cognitive performance and regional brain metabolism, suggesting a potential link between chronic immune dysregulation and neurocognitive impairment in post-COVID-19. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with an increased risk of portal vein thrombosis (PVT), which may negatively affect post-liver transplant (LT) outcomes. We aimed to evaluate the impact of PVT on post-LT outcomes in MASLD versus non-MASLD recipients and assess outcomes in MASLD patients with PVT who received donation after circulatory death (DCD) grafts. Methods: Using the UNOS database, we analyzed adult LT recipients from 2002 to 2022. Kaplan–Meier and Cox regression models were used to assess one-year post-LT outcomes. Results: Among 46,933 LT recipients, 20% had MASLD (15% PVT prevalence) and 80% had non-MASLD etiologies (9% PVT prevalence). Overall, 3051 recipients (6.5%) received DCD grafts. PVT at the time of transplant was associated with significantly higher risks of all-cause mortality, graft failure, and death-censored graft failure (DCGF) in both MASLD and non-MASLD groups (p < 0.05), although no significant differences were observed between the two groups. In the DCD subgroup, MASLD recipients with PVT had a significantly higher risk of all-cause mortality compared to non-MASLD recipients without PVT (adjusted hazard ratio [aHR] 2.24, 95% CI 1.17–4.28, p = 0.01), but no differences were observed for graft failure or DCGF. Conclusions: PVT at the time of transplant is associated with poorer survival in MASLD and non-MASLD recipients. No difference was found between the two groups. In candidates receiving DCD grafts, the presence of PVT at time of transplant was associated with a marked increase in mortality risk, although this finding requires further validation in larger cohorts. Full article

Recognition and binding to β-galactose-containing carbohydrates and lipids are crucial for several fundamental biological processes that are mediated primarily by a family of proteins known as galectins (S-type lectins). Galectins in the human placenta regulate critical processes such as maternal–fetal immune tolerance, trophoblast invasion, vascular remodeling and angiogenesis, ensuring proper fetal development and preventing pregnancy complications such as preeclampsia and miscarriage. Gestational diabetes mellitus (GDM) is a widespread complication of pregnancy, affecting approximately 1 in 7 pregnancies, and its incidence is increasing globally, indicating a particularly strong association with the obesity pandemic. Profiles of placental expression and distribution of individual galectins significantly change during the course of GDM. This is accompanied by placental dysfunction, which is especially severe with poor glycemic control. The aim of this review is to present the current state of knowledge on the involvement of abnormal galectin signaling in the pathomechanisms of GDM-associated placental dysfunction. Further research is needed to determine whether changes in placental galectins occur secondary to metabolic abnormalities in GDM or are involved as a primary cause. Galectins present in placental tissue and serum should be validated as potential biomarkers of GDM. Full article

Mechanobiology has emerged as a unifying framework for understanding how mechanical forces and tissue physical properties regulate cellular function, metabolism, and disease progression. Mechanical forces are fundamental regulators of cellular behaviour and tissue homeostasis. Growing evidence indicates that disturbances in mechanobiological signalling contribute to both metabolic disorders and cardiovascular diseases, two highly prevalent and interrelated groups of conditions. This review aims to synthesize current evidence on mechanobiological mechanisms linking metabolic dysfunction and cardiovascular pathology, with particular emphasis on shared pathways involved in tissue remodelling, inflammation, and disease progression. Shared pathogenic mechanisms, including chronic low-grade inflammation, oxidative and endoplasmic reticulum stress, and lipotoxicity, further reinforce the bidirectional relationship between metabolic and cardiovascular disorders. Moreover, advances in mechanobiological imaging and the usage of mechanobiological biomarkers are more commonly regarded as promising tools for early detection of the disease and risk stratification. It is worth mentioning that targeting mechanosensitive pathways may support the development of personalised diagnostic strategies and novel therapeutic approaches addressing both metabolic and cardiovascular components of disease, which may result in a breakthrough. Full article

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is the most prevalent chronic liver disorder globally. Mazdutide has shown clinical benefits in weight management and metabolic regulation, indicating its potential as a therapeutic agent for MASLD. This study aimed to investigate the efficacy and mechanism of action of Mazdutide against early-stage MASLD. Methods: A MASLD mouse model was induced by a 12-week high-fat diet, followed by a 4-week treatment with subcutaneous Mazdutide (100, 200, or 400 μg/kg). In vitro, a cellular MASLD model was established by treating hepatocytes with 1 mM free fatty acids for 24 h, followed by co-treatment with Mazdutide (10, 20, or 50 nM) or the endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid (4-PBA). Serum and hepatic lipid profiles, liver injury markers, and pro-inflammatory cytokines were quantified. Liver histopathology was assessed by hematoxylin and eosin and Oil Red O staining. Protein expression related to ER stress, inflammation, and lipid metabolism was analyzed by immunohistochemistry and Western blot. Results: Compared with the MASLD model group, Mazdutide treatment significantly ameliorated systemic and hepatic lipid metabolism disorders, reduced liver injury markers and hepatic steatosis, and mitigated inflammation and oxidative stress in MASLD mice and hepatocytes (p < 0.05). Mechanistically, Mazdutide alleviated ER stress by modulating the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway, suppressed the nuclear Factor kappa B (NF-κB)-mediated inflammatory response, and downregulated the expression of key lipogenic regulators including sterol regulatory element-binding protein 1 (SREBP-1), CCAAT/enhancer-binding protein beta (C/EBPβ), and peroxisome proliferator-activated receptor gamma (PPARγ) in both models (p < 0.05). Conclusions: Our findings demonstrate that Mazdutide alleviates hepatic ER stress in MASLD, suppresses inflammatory responses and improved lipid metabolism, which ultimately attenuates disease progression. Full article

Myocardial ischemia–reperfusion injury remains a major unresolved challenge in cardiovascular medicine. Although timely restoration of blood flow is essential to limit ischemic damage, reperfusion triggers a complex network of maladaptive biological responses, including oxidative stress, calcium overload, mitochondrial dysfunction, metabolic impairment, and sterile inflammation. These processes converge on cardiomyocyte death, adverse ventricular remodeling, and long-term functional deterioration. Mesenchymal stem cells have been widely investigated as cardioprotective agents; however, accumulating evidence indicates that their beneficial effects are predominantly mediated by paracrine mechanisms. Among these, extracellular vesicles released by mesenchymal stem cells have emerged as key biological effectors. Experimental studies demonstrate that mesenchymal stem cell–derived extracellular vesicles modulate multiple signaling pathways involved in ischemia–reperfusion injury, including activation of the phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB) axis, regulation of signal transducer and activator of transcription 3 (STAT3) signaling in a cell-specific manner, suppression of nuclear factor kappa B (NF-κB)-driven inflammatory responses, and stabilization of hypoxia-inducible factor-1α (HIF-1α)–dependent adaptive programs. At the subcellular level, these vesicles preserve mitochondrial structure and function, support energy metabolism, regulate mitophagy, and limit oxidative damage. Their molecular cargo, comprising regulatory microRNAs, metabolic enzymes, and stress-response proteins, enables coordinated modulation of survival, inflammatory, and reparative pathways rather than single-target effects. This review synthesizes current experimental evidence on the mechanistic basis of mesenchymal stem cell–derived extracellular vesicle–mediated cardioprotection and discusses their potential as cell-free, mechanism-based therapeutic strategies to limit myocardial ischemia–reperfusion injury. Full article