Amphiregulin as a central dynamic network biomarker in inhaled polyhexamethylene guanidine triggered pulmonary...

The widespread application of disinfectants has significantly curbed infectious diseases yet prompted rising concerns regarding potential threats to human health and ecosystems. Polyhexamethylene guanidine (PHMG), first identified as a hazardous agent in humidifier disinfectants, was linked to an outbreak of pulmonary fibrosis in South Korea. However, the early molecular mechanisms driving PHMG-induced fibrosis remain poorly understood. Here, longitudinal transcriptomic analyses and dynamic network biomarker (DNB) theory were applied in a mouse model exposed to PHMG aerosol to uncover critical molecular events preceding fibrosis onset. This approach revealed 205 genes strongly associated with PHMG-induced pulmonary fibrosis, underscored by peak Ir and Is values at 4th week-a key turning point in pathogenesis. Network topology and pathway assessments pinpointed AREG as a principal DNB molecule, corroborated by its early upregulation relative to classical fibrosis markers α-SMA and TGF-β1. In parallel, its receptor EGFR showed elevated phosphorylation by 4th week. Notably, targeted inhibition of AREG markedly attenuated PHMG-induced pulmonary fibrosis. Collectively, these findings underscore the necessity of identifying preclinical molecular perturbations to enable timely therapeutic intervention. By delineating AREG's early role in the fibrotic cascade, this study advances the mechanistic understanding of PHMG-induced fibrosis and proposes a promising target for anti-fibrotic strategies.