International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 20-32 http://medscipublisher.com/index.php/ijmms 23 The metabolic reprogramming of immune cells, particularly macrophages, in CF patients further exacerbates inflammation. The IRE1α-XBP1 pathway activation in these cells leads to increased glycolytic rates and mitochondrial function, resulting in excessive production of pro-inflammatory cytokines such as TNF and IL-6. This hyper-inflammatory state is a hallmark of CF and underscores the importance of targeting metabolic pathways to modulate inflammation and improve clinical outcomes (Esther et al., 2015; Lara-Reyna et al., 2019). 3.3 The interplay between metabolic dysfunction and chronic disease in CF Metabolic dysfunction plays a crucial role in the chronic disease state of CF. The defective CFTR protein not only affects ion transport but also disrupts various metabolic pathways. For instance, CF patients exhibit altered lipid metabolism and defective autophagy, which impair the clearance of internalized pathogens and contribute to chronic infections. Therapeutic interventions targeting sphingolipid synthesis have shown promise in reducing inflammation and promoting autophagy, thereby improving pathogen clearance and overall metabolic health in CF patients (Mingione et al., 2020a). Additionally, the dysregulation of glucocorticoid metabolism in CF patients indicates a broader metabolic imbalance. The decreased activity of enzymes involved in cortisol metabolism and the increased conversion of cortisone to cortisol suggest an adaptive mechanism to counteract reduced adrenal steroid synthesis. This metabolic adaptation may influence the overall energy balance and nutritional status of CF patients, highlighting the need for comprehensive therapeutic strategies that address both metabolic and inflammatory aspects of the disease (Podgórski et al., 2022). 4 Metabolic Dysregulation in Cystic Fibrosis 4.1 Lipid metabolism Cystic Fibrosis (CF) is associated with significant abnormalities in lipid metabolism, particularly in the processing of fatty acids. Defective CFTR function affects the metabolism of fatty acids, cholesterol, and sphingolipids, leading to an accumulation of inflammatory lipids such as ceramide. This accumulation is linked to increased inflammation and susceptibility to infections (Worgall, 2009; Mingione et al., 2020a; Signorelli et al., 2021). Myriocin, an inhibitor of sphingolipid synthesis, has been shown to reduce inflammation and enhance fatty acid oxidation, suggesting a potential therapeutic approach for managing lipid-related inflammation in CF (Figure 2) (Mingione et al., 2020a; Mingione et al., 2020b; Signorelli et al., 2021). Lipid depletion in CF patients can impair the function of immune cells, particularly macrophages and monocytes. The dysregulation of lipid metabolism affects the immune response, leading to chronic inflammation and reduced pathogen clearance. Myriocin treatment has been shown to modulate lipid storage and enhance the immune response by promoting autophagy and lipid oxidation, thereby improving the function of immune cells in CF atients (Lara-Reyna et al., 2019; Mingione et al., 2020a; Signorelli et al., 2021). 4.2 Carbohydrate metabolism CF-Related Diabetes (CFRD) is a common complication in CF patients, characterized by both insulin deficiency and insulin resistance. The pathophysiology of CFRD involves chronic inflammation, oxidative stress, and the direct impact of CFTR dysfunction on pancreatic beta cells. These factors contribute to impaired glucose metabolism and the development of diabetes in CF patients (Lara-Reyna et al., 2019; Feng et al., 2023). Glucose dysregulation in CF patients can exacerbate lung function decline. Hyperglycemia can promote bacterial growth in the lungs, leading to increased infection rates and inflammation. Additionally, the metabolic stress associated with CFRD can further impair lung function, creating a vicious cycle of metabolic and respiratory complications (Lara-Reyna et al., 2019; Feng et al., 2023). 4.3 Protein and energy metabolism CF patients often experience hypermetabolism and malnutrition due to increased energy expenditure from chronic inflammation and recurrent infections. This hypermetabolic state can lead to significant weight loss and muscle wasting, further compromising the overall health and quality of life of CF patients (Lara-Reyna et al., 2019; Feng et al., 2023).
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