Abstract Chronic kidney disease (CKD) produces a distinctive cardiovascular phenotype that traditional risk factors cannot fully explain. Fibroblast growth factor 23 (FGF23) rises early in CKD, whereas renal and circulating α-Klotho decline; this imbalance weakens canonical FGFR1c–α-Klotho signalling and permits maladaptive receptor engagement in cardiovascular tissues. The present review synthesises current evidence on cell-type-specific FGF23 signalling in CKD, focusing on receptor topology, intracellular signalling cascades, and therapeutic implications. In vascular endothelial cells, excess FGF23 promotes oxidative stress, depletes nitric oxide, and impairs endothelial function, partly through FGFR1–PLCγ2–NOX2-dependent generation of reactive oxygen species. In vascular smooth muscle cells, FGF23 intersects with MEK–ERK signalling and phosphate sensing, although medial calcification is driven predominantly by phosphate retention and α-Klotho deficiency rather than by FGF23 alone. In cardiomyocytes, α-Klotho-independent FGFR4 signalling activates the PLCγ–calcineurin–NFAT axis, promoting left ventricular hypertrophy, calcium-handling abnormalities, and arrhythmogenic vulnerability. FGF23 also contributes to cardiac fibroblast activation and extracellular-matrix remodelling. A parallel, largely FGF23-independent calcium-sensing receptor–calcium–organelle stress pathway may additionally amplify mitochondrial injury, cGAS–STING signalling, and inflammasome-mediated cell death within the CKD–mineral bone disorder (CKD-MBD) milieu. Emerging experimental evidence that skeletal muscle can generate FGF23 during phosphate stress broadens the traditional bone-centred model of CKD-MBD. Calciprotein particles are additionally implicated as an extracellular signal coupling mineral loading to FGF23 secretion, and prognostic data from naturally occurring feline CKD support a conserved clinical relevance across species. Current therapies lower FGF23 only indirectly, through phosphate, parathyroid hormone, iron, and kidney-protective pathways, and dedicated cardiovascular outcome trials targeting the FGF23–α-Klotho axis are still lacking.
Abstract Air pollution, particularly fine particulate matter (PM2.5), has emerged as an important yet under-recognised environmental contributor to cognitive decline and Alzheimer’s disease (AD) across the life course. Although epidemiological studies consistently associate long-term PM2.5 exposure with impaired cognition, from reduced neurodevelopmental performance in children to accelerated neurodegeneration in older adults, the biological mechanisms linking inhaled particles to AD-related brain pathology remain incompletely defined. In the present review, we synthesise current epidemiological and experimental evidence to position the lung-brain axis as a central mechanistic framework through which PM2.5 may influence brain aging and AD pathogenesis. Rather than acting solely through direct particle entry into the brain, PM2.5-induced pulmonary injury initiates systemic signalling cascades, including inflammatory mediators, oxidative stress, blood-brain barrier disruption, and extracellular vesicle-mediated intercellular communication, which together propagate disease signals from the lung to the brain. We further examine how these pathways intersect with core AD-related processes, including amyloid-β accumulation, tau pathology, impaired protein clearance, maladaptive microglial responses, and autophagy-lysosomal dysfunction. We also discuss important modifiers of susceptibility and heterogeneity in reported associations, including pollutant composition, co-exposure to other air pollutants, sex, APOE genotype, and epigenetic reprogramming. Overall, the present review proposes an integrated multi-organ model of PM2.5 neurotoxicity that aligns environmental exposure with key mechanisms of AD pathogenesis and highlights priorities for strengthening causal inference and future translational research.
Abstract The circadian clock orchestrates the internal timing of numerous physiological processes through an approximately 24-h cycle. It comprises a hypothalamic central clock, which responds to light cues and entrains peripheral clocks within individual cells and organs that, depending on the tissue, regulate gene expression across diverse biological functions in a tissue-specific manner. Peripheral clocks are also entrained by feeding and exercise-related cues, enabling their synchronization with feeding rhythm and physiology. Together, these clocks maintain a complex molecular network essential for metabolic homeostasis. Disruption of circadian rhythms, driven by genetic, environmental, or behavioral factors, is increasingly recognized as a major contributor to cardiometabolic disorders. Modern lifestyles, including shift work, irregular sleep, prolonged exposure to artificial light at night, jet lag, and erratic eating schedules, misalign circadian clocks with environmental cues, contributing to disruption of circadian rhythms or chronodisruption. This misalignment alters hormonal regulation, promotes systemic inflammation, and impairs metabolic balance, thereby increasing the risk of cardiovascular disease, obesity, type 2 diabetes, and related complications. The present review examines the mechanistic roles of core circadian clock genes in cardiometabolic health, highlighting their regulation of physiological processes in peripheral organs such as the heart, liver, and adipose tissue. We further discuss how circadian clock disruption accelerates disease onset and progression and explore emerging therapeutic strategies, including pharmacological modulation of the molecular circadian clock components and personalized chronotherapy. These approaches offer promising avenues to restore circadian alignment and mitigate cardiometabolic risk.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with higher incidence of hepatic neoplasia and may influence the tumor microenvironment through immune–metabolic mechanisms. In this study, the contribution of intrahepatic natural killer T (NKT) cells and the LIGHT/LTβR/HVEM axis to MASLD severity in patients with primary hepatic cancer (PHC) or colorectal cancer liver metastases (CRCLM) was investigated. Liver biopsies were analyzed and stratified by intrahepatic triglyceride (TG) content into Group I (LIGHT/LTBR/HVEM expression were assessed. Group II showed higher MASLD activity score (MAS), with the greatest score in CRCLM patients. Fibrosis percentage did not differ between groups, although MMP9 and SOX9 gene expression was elevated in Group II, consistent with enhanced extracellular matrix remodeling. The LIGHT/LTBR/HVEM axis gene expression did not differ between groups, but PHC patients from Group II displayed increased LIGHT/LTBR gene expression. Hepatic NKT2 cells were significantly elevated in Group II, more pronounced in CRCLM. In group II, NK-cell abundance inversely correlated with HVEM expression, an association that remained significant after FDR correction. In addition, TP53 mRNA levels were positively associated with expression of components of the LIGHT/LTBR/HVEM axis. Our data reveal associations between MASLD severity, intrahepatic immune-cell composition and the LIGHT/LTBR/HVEM pathway in patients with hepatic neoplastic disease, supporting further investigation of NKT cell subsets and LIGHT signaling as potential markers of the immune–metabolic alterations accompanying steatotic liver disease in this setting.
