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Male breast cancer is a rare but increasingly recognized disease with limited data on modifiable risk factors. Specifically, it is not known if the inverse association between cardiorespiratory fitness (CRF) and breast cancer risk reported in women is similar to the association between CRF and breast cancer in men. The study aimed to evaluate the association between CRF and the incidence of male breast cancer in a large, nationally representative cohort of U.S. Veterans. We analyzed data from 777,618 male Veterans who completed an exercise treadmill testing (ETT) between 1999 and 2024 within the Veterans Health Administration and had no evidence of breast cancer prior to the ETT. CRF was expressed in peak metabolic equivalents (METs). The cohort was categorized into 4 age-adjusted CRF categories based on the peak METs achieved. The primary outcome was incident male breast cancer, ascertained through the Veterans Affairs Computerized Patient Record System. Cox proportional hazards models were used to estimate hazard ratios (HRs) for breast cancer incidence across CRF categories, adjusted for age, race, body mass index, hypertension, diabetes (T2DM), chronic kidney disease, smoking, and alcohol use. Over a median follow-up of 10.7 years 518 men were diagnosed with breast cancer. After multivariable adjustment, age (HR = 1.24, 95% confidence interval (95%CI): 1.14-1.36) per decade, chronic kidney disease (HR = 2.13; 95%CI:1.41-3.23), hypertension (HR = 1.57; 95%CI: 1.28-1.92), T2DM (HR = 1.24; 95%CI: 1.02-1.51), and poor CRF (HR = 1.69; 95%CI: 1.24-2.30) were the strongest predictors of breast cancer. Compared to patients in the lowest CRF category, breast cancer risk was 41% lower for individuals in the highest CRF quartile (HR = 0.59; 95%CI: 0.44-0.81). Higher CRF was independently associated with a substantially lower risk of breast cancer in men. These findings suggest that CRF may represent a modifiable risk factor in the prevention of male breast cancer, underscoring the broader importance of physical fitness in reducing cancer risk across sexes.

Excessive dietary fructose consumption contributes to the rapidly increasing prevalence of obesity, metabolic syndrome, and chronic kidney disease worldwide, and accumulating preclinical evidence has confirmed that excess fructose exposure provokes severe mitochondrial dysfunction, which serves as a critical upstream driver of progressive metabolic disturbance and renal tissue injury. Conventionally, fructose-induced mitochondrial damage is thought to originate from harmful intermediate metabolites produced during intracellular fructose catabolism, while the potential direct pathogenic effect of intact unmetabolized fructose is largely overlooked. It remains unclear whether free fructose can directly target core mitochondrial complexes to initiate functional defects independent of its metabolic breakdown. Here, we report a fructose metabolism-independent mechanism in which fructose structurally remodels the translocase of the outer membrane (TOM) complex, obstructing the import of nuclear-encoded mitochondrial proteins and inhibiting mitochondrial ribosome biogenesis as well as oxidative phosphorylation. In vitro biochemical assays confirm that fructose non-covalently binds to TOM22 and induces subtle but functionally critical conformational changes in the TOM complex, thereby blocking the transmembrane translocation of mitochondrial ribosome subunits. Notably, disrupting the fructose-TOM22 binding efficiently recovers abnormal ribosome trafficking, restores compromised oxidative phosphorylation, and ameliorates mitochondrial dysfunction and glomerular pathological lesions in fructose-treated podocytes and mouse injury models. Our findings establish an innovative mechanistic paradigm that fructose acts as a direct allosteric modulator of mitochondrial membrane complexes, identifying TOM structural remodeling as a previously unrecognized molecular trigger of fructose-associated mitochondrial and metabolic disorders.

Chronic kidney disease (CKD) affects more than 850 million people worldwide, and progressive renal fibrosis is the most common cause of irreversible renal loss. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are nanoscale membrane-bound particles carrying bioactive proteins, lipids, and regulatory RNAs across biological barriers. Target cells are EVs that enter via membrane receptors and endocytic/fusion pathways and provide cargo delivery and modulation of downstream signaling. Engineering techniques such as genetic modification of parent cells, chemical surface functionalization, stimuli-responsive materials, and synthetic materials have improved the therapeutic potential of MSC-EVs by improving tissue targeting and antifibrotic activity. This review summarizes MSC-EV colloidal biology, biogenesis, surface properties, cargo composition, and engineered modifications for antifibrotic applications. Mechanisms that inhibit fibrosis, such as suppression of the TGF-β/Smad pathway, reversal of epithelial-mesenchymal transition, and modulation of macrophage behavior at the tissue-vesicle interface, are discussed. Effects of donor cell preconditioning and microenvironmental factors on surface properties and therapeutic potency are discussed. This paper is a paradigm shift from traditional biology to precision nanomedicine engineering using colloidal surface chemistry, biointerface dynamics, and translational manufacturing. We bridge material science with renal pathophysiology to develop a rational roadmap for future clinically available EV therapeutics targeting multifactorial renal fibrotic diseases.

Chronic kidney disease (CKD) is associated with uraemic cardiomyopathy characterised by early metabolic dysfunction. Elevated myocardial intracellular sodium (Naᵢ) has emerged as a driver of cardiometabolic remodelling, however, its role in CKD and therapeutic modulation remains unclear. We investigated whether dual sodium-glucose cotransporter (SGLT)1/2 inhibition with sotagliflozin (SOTA) targets Naᵢ and improves cardiac metabolism in CKD. CKD was induced in male Wistar rats by 5/6 nephrectomy and assessed after 4 weeks. Cardiac phenotype was evaluated using in vivo echocardiography and ex vivo Langendorff perfusion combined with 23Na and 31P NMR spectroscopy. CKD hearts exhibited preserved systolic but impaired diastolic function and a marked elevation in myocardial Naᵢ, identifying Naᵢ overload as an early feature of uraemic cardiomyopathy. Cardiac metabolomic profiling and flux modelling demonstrated widespread suppression of central carbon metabolism, redox imbalance despite preserved PCr/ATP. In silico electrophysiological simulations predicted Naᵢ-driven Ca2+ dysregulation consistent with in vivo diastolic dysfunction. Chronic SOTA treatment (3 weeks, in vivo) normalised myocardial Naᵢ and partially reversed metabolic remodelling. Acute SOTA exposure (20-minute, Langendorff-perfusion) similarly reduced Naᵢ in CKD hearts but not in controls, indicating a direct, disease-selective myocardial effect. Naᵢ normalisation was accompanied by improved redox state and restoration of mitochondrial metabolic flux, without changes in expression of canonical Na + -handling proteins. Myocardial Naᵢ overload emerges as an early and potentially modifiable feature of uraemic cardiomyopathy. Dual SGLT1/2 inhibition with SOTA directly lowers Naᵢ and improves cardiac metabolic homeostasis, supporting Naᵢ as a mechanistically relevant and potentially targetable pathway in CKD-related cardiac remodelling.