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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.<\/jats:p>","DOI":"10.1007\/s00210-026-05265-1","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T01:52:34Z","timestamp":1775526754000},"page":"12935-12951","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting of MAPK\u2013ERK1\/2 signaling by metformin in asthma: an updated mechanistic insight"],"prefix":"10.1007","volume":"399","author":[{"given":"Manal Ewaiss","family":"Hassan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayder M.","family":"Al-kuraishy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2206-7236","authenticated-orcid":false,"given":"Athanasios","family":"Alexiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9020-874X","authenticated-orcid":false,"given":"Marios","family":"Papadakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1827-6131","authenticated-orcid":false,"given":"Safaa A.","family":"Faheem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman K.","family":"Rashwan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7817-425X","authenticated-orcid":false,"given":"Gaber El-Saber","family":"Batiha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"5265_CR1","first-page":"1","volume":"94","author":"LJ Akinbami","year":"2012","unstructured":"Akinbami LJ et al (2012) Trends in asthma prevalence, health care use, and mortality in the United States, 2001\u20132010. 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