Environmentally relevant phthalic acid exposure promotes pulmonary fibrogenesis through IL-1α/NF-κB pathway:...

Phthalate esters (PAEs), widely used as plastic additives in consumer products such as food packaging, can be metabolized to phthalic acid (PTA) in vivo. However, the potential contribution of PTA to respiratory fibrotic processes remains poorly understood. In this study, we investigated the effects and underlying mechanisms of PTA on pulmonary fibrogenesis using human lung fibroblast IMR-90 cells chronically exposed to environmentally relevant concentrations of PTA (0-60 μg/L) for 14 days. PTA exposure promoted pro-fibrotic responses and cellular senescence, as evidenced by increased expression of fibrosis-associated markers, enhanced senescence-associated β-galactosidase activity, and upregulation of CDKN2A. Proteomic profiling and functional perturbation experiments further implicated the IL-1α/NF-κB/SASP signaling axis in these responses. PTA-induced senescence and pro-fibrotic effects were attenuated by inhibition of NF-κB signaling and IL-1 signaling, supporting the functional involvement of this pathway. In a bleomycin-induced progressive pulmonary fibrosis model, subsequent PTA exposure further aggravated collagen deposition and increased the pulmonary expression of fibrosis-, senescence-, and Il-1a/Nf-κb-associated genes, providing in vivo support for the biological relevance of the pathway identified in vitro. Molecular docking additionally predicted a potential interaction between PTA and IL-1α. Therefore, these findings offer novel mechanistic insights into environmental pollutant-induced fibrogenesis.