N-acetylcysteine inhibits gene and protein expression of MUC5AC in COPD-relevant human models: evidence from a meta-analysis.

Chronic mucus hypersecretion is highly prevalent in chronic obstructive pulmonary disease and is associated with worse outcomes. MUC5AC is a key inducible gel-forming mucin driving pathological mucus overproduction. N-acetylcysteine (NAC) is widely used as a mucolytic and exhibits antioxidant and anti-inflammatory properties. Its quantitative impact on MUC5AC regulation has not been formally synthesized. We performed a systematic review and meta-analysis (OSF registration ID: 2vym4) of original studies evaluating the effect of NAC on MUC5AC gene and protein expression in human respiratory cell models of mucus hypersecretion. Standardized mean differences with 95% CIs were pooled using DerSimonian-Laird random-effects models. Heterogeneity, publication bias, sensitivity analyses, and random-effects meta-regression on NAC dose were conducted. Fifteen articles were included. NAC significantly reduced MUC5AC mRNA (standardized mean difference -1.30, 95% CI: -1.61 to -0.98; I2=37.07%), without significant dose-response. NAC produced very large reductions in extracellular (-2.70, 95% CI: -3.29 to -2.11; I2=48.89%) and intracellular (-2.38, 95% CI: -3.27 to -1.48; I2=67.35%) MUC5AC protein, with significant dose-response relationships for both. After sensitivity analyses, the pooled protein effect remained very large (-2.00, 95% CI: -2.38 to -1.62; I2=25.63%). Funnel plots and Egger's tests suggested publication bias, which diminished after exclusion of influential comparisons. NAC robustly inhibits MUC5AC gene and protein expression in human pre-clinical models of mucus hypersecretion, supporting a strong mucoregulatory action that complements mucolytic and antioxidant effects. These data reinforce the rationale for NAC use in chronic obstructive pulmonary disease patients with a hypersecretory phenotype.