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Fixed airflow limitation (FAO), prevalent in patients with severe or difficult-to-treat asthma, is mainly caused by airway remodeling. Airway remodeling is initiated by inflammation and involves subsequent pathological changes. Glycyl- l -histidyl- l -lysine (GHK) is a matrikine with anti-inflammatory and antioxidant effects, naturally existing in human tissue. At present, the GHK level in human plasma and whether it is related to airway remodeling of asthma remain unclear. This study was conducted to determine how GHK is involved in airway remodeling in asthma. Our result showed that the plasma GHK levels of patients with asthma were significantly lower than those of age-matched healthy controls. In asthma patients, plasma GHK levels display a moderate correlation with FEF 25–75% , and patients with FAO had significantly lower GHK levels. Ovalbumin-induced mice of asthma model treated with PBS or GHK-Cu (a form of GHK with higher bioavailability) were used to evaluate the effect of exogenous GHK supplement on airway remodeling. GHK-Cu administration alleviated airway remodeling, as reflected by decreased peribronchial collagen deposition and airway mucus secretion, and suppressed epithelial-mesenchymal transition. The therapeutical effect related to decreased TGF-β1 level. Successively, network pharmacology and the validation data of experiments in vivo and vitro demonstrated that GHK-Cu decreased TGF-β1 level by increasing SIRT1 expression and activating SIRT1 deacetylation in airway epithelial cells, thereby alleviating airway remodeling. Collectively, decreased plasma GHK levels were related to FAO in asthma patients. Through the direct binding and activation of SIRT1, exogenous GHK-Cu administration alleviated airway remodeling in asthmatic mice. [Display omitted] • Decreased plasma GHK levels are related to fixed airflow limitation in asthma patients. • GHK-Cu protects against airway remodeling via direct binding and activation of SIRT1. • Exogenous GHK-Cu administration alleviates airway remodeling in asthmatic mice. [ABSTRACT FROM AUTHOR]