AMPK-mediated modulation of JAK2/STAT3 signaling in asthma: a promising target for controlling airway inflammation and remodeling

To highlight the therapeutic potential of targeting the AMPK/JAK2/STAT3 signaling axis in severe asthma, particularly neutrophilic and steroid-resistant forms, where current therapies such as corticosteroids show limited long-term effectiveness. This review examines current evidence on the role of the AMPK/JAK2/STAT3 pathway in asthma pathogenesis, with emphasis on its involvement in airway inflammation, immune dysregulation, and airway remodeling. It also evaluates the potential of pharmacologic modulators, especially AMPK activators such as metformin and JAK inhibitors, as targeted therapeutic strategies. The JAK2/STAT3 axis promotes pro-inflammatory type 2 and type 17 immune responses, airway inflammation, and structural airway changes. In contrast, AMPK acts as an anti-inflammatory regulator that can suppress excessive STAT3 activation and help restore immune balance. Available evidence suggests that activation of AMPK, particularly by metformin, alone or in combination with JAK inhibitors, may reduce cytokine release, modulate immune cell differentiation, and limit pathologic cellular remodeling in asthma. Targeting the AMPK/JAK2/STAT3 axis may provide a unified and promising therapeutic approach for severe, treatment-resistant asthma. Although current findings support the clinical potential of this strategy, further studies are needed to clarify the underlying mechanisms in human asthma and to optimize its application within a precision medicine framework.