Targeting of MAPK-ERK1/2 signaling by metformin in asthma: an updated mechanistic insight.

Asthma is a heterogeneous chronic inflammatory airway disease characterized by persistent inflammation, dysregulated immune signaling, and progressive airway remodeling. It has been shown that asthma pathogenesis involves multiple signaling pathways. It has been illustrated that the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) cascade, which emerges as a central regulator linking immune activation, epithelial dysfunction, and structural remodeling of the airway, is implicated in the pathogenesis of asthma. Sustained ERK1/2 activation is consistently demonstrated in human asthmatic airways and experimental models, correlating with disease severity, inflammatory cell infiltration, and corticosteroid resistance. This review provides a comprehensive and critical discussion of the ERK1/2 signaling in asthma, spanning immune cells, airway epithelium, and airway smooth muscle. We evaluate preclinical and translational evidence supporting ERK1/2 as a therapeutic target and examine emerging pharmacological strategies, including indirect pathway modulation via AMP-activated protein kinase (AMPK) activation and drug repositioning with the anti-diabetic metformin. By integrating mechanistic insights with therapeutic implications, this review positions ERK1/2 as a pivotal signaling node for precision targeting in severe, treatment-refractory asthma.