Corticosteroid insensitivity in obese asthma: potential mechanisms and therapeutic perspectives

Asthma is a heterogeneous condition influenced by multiple clinical and biological factors, and obesity has emerged as a major modifier that worsens symptoms and increases the risk of exacerbations. This review aimed to examine the mechanisms by which obesity contributes to reduced responsiveness to corticosteroids, which remain the cornerstone of guideline-based asthma management. We reviewed evidence from clinical and experimental studies describing how adipose tissue dysfunction, chronic low-grade inflammation, oxidative stress, and systemic comorbidities alter glucocorticoid receptor signalling and downstream pathways. Particular attention was given to immune mechanisms such as neutrophilic inflammation and interleukin-17 signalling, as well as metabolic disturbances including hyperleptinaemia and vitamin D deficiency. We also considered the role of lifestyle factors, such as physical inactivity and dietary patterns, in sustaining corticosteroid insensitivity. Based on these insights, we evaluated both established and emerging therapeutic strategies, including weight loss, structured exercise, dietary modification, and drug repurposing with agents such as metformin, low-dose theophylline, and glucagon-like peptide-1 receptor agonists. A comprehensive synthesis of these findings highlights the need for integrated lifestyle and pharmacological interventions, and provides a framework for the development of targeted treatments to improve outcomes in patients with obesity-associated, corticosteroid-insensitive asthma.