International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 20-32 http://medscipublisher.com/index.php/ijmms 27 and animal models, paving the way for future clinical applications (Ntimbane et al., 2009; Checa et al., 2021). This approach offers a potential cure for CF by addressing the root cause of the disease at the genetic level (Cantin et al., 2007; Hector et al., 2014). mRNA-based therapies represent another innovative approach to treating CF. These therapies involve delivering synthetic mRNA encoding the functional CFTR protein to the patient's cells, thereby bypassing the defective gene. This strategy has shown promise in preclinical studies, with evidence of restored CFTR function and improved cellular health (Ntimbane et al., 2009; Checa et al., 2021). mRNA-based therapies offer a versatile and potentially less invasive alternative to gene editing, with the potential for rapid translation to clinical use (Cantin et al., 2007; Di Pietro et al., 2020). 7 Challenges in Addressing Metabolic Dysregulation 7.1 Difficulty in targeting systemic metabolic pathways while managing localized disease effects One of the primary challenges in addressing metabolic dysregulation in Cystic Fibrosis (CF) is the difficulty in targeting systemic metabolic pathways while simultaneously managing localized disease effects. CF is characterized by mutations in the CFTR gene, leading to a range of systemic and localized complications, particularly in the lungs and digestive system. The metabolic reprogramming observed in CF, such as increased glycolytic rates and mitochondrial function in macrophages, exacerbates inflammation and complicates therapeutic interventions (Lara-Reyna et al., 2019). This systemic metabolic dysregulation needs to be carefully balanced with localized treatments to avoid unintended consequences. Moreover, the complexity of CF pathology, which includes chronic inflammation, infection, and mucus obstruction, necessitates a multifaceted approach to therapy. Targeting systemic metabolic pathways without exacerbating localized disease effects is challenging due to the interconnected nature of metabolic and inflammatory pathways. For instance, the IRE1α-XBP1 pathway, which regulates both metabolic and inflammatory responses, highlights the difficulty in isolating metabolic interventions from their broader physiological impacts (Bodas and Vij, 2019; Lara-Reyna et al., 2019). 7.2 Variability in patient responses to therapies Another significant challenge in addressing metabolic dysregulation in CF is the variability in patient responses to therapies. CFTR mutations are highly heterogeneous, with over 2 000 different mutations identified, leading to diverse clinical manifestations and responses to treatment (Bardin et al., 2018; Mall et al., 2019). This genetic variability means that a one-size-fits-all approach is often ineffective, and personalized medicine becomes crucial. For example, while CFTR modulators have shown promise, their efficacy can vary significantly among patients depending on their specific CFTR mutations (Mall et al., 2019). Additionally, the metabolic state of immune cells in CF patients can differ, further complicating treatment strategies. Some patients may exhibit heightened ER stress and metabolic reprogramming in their immune cells, while others may not (Lara-Reyna et al., 2019). This variability necessitates a tailored approach to therapy, taking into account individual metabolic profiles and genetic backgrounds to optimize treatment outcomes. 7.3 Adverse effects and long-term sustainability of metabolic interventions The adverse effects and long-term sustainability of metabolic interventions pose another challenge in managing CF. Many metabolic therapies, while effective in the short term, can have significant side effects that limit their long-term use. For instance, targeting the IRE1α pathway to reduce inflammation and metabolic dysregulation in CF macrophages has shown promise, but the potential for off-target effects and toxicity remains a concern (Lara-Reyna et al., 2019). Similarly, therapies targeting systemic metabolic pathways, such as those involved in glycolysis and lipid metabolism, must be carefully monitored to avoid adverse effects on other organs and systems (Ung et al., 2021). Furthermore, the long-term sustainability of these interventions is uncertain. Chronic diseases like CF require ongoing treatment, and the cumulative effects of long-term metabolic modulation are not fully understood. There is a need for continuous research to develop safer and more sustainable therapeutic options that can be maintained
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