Environmental nitro-aromatic compounds link pulmonary fibrosis through BCL2L1 structural destabilization

Nitro-aromatic compounds (NACs) are pervasive environmental pollutants with recognized pulmonary toxicity, yet their mechanistic involvement in pulmonary fibrosis remains incompletely understood.

We applied an integrative framework combining network toxicology, transcriptomic analysis, prognostic modeling, immune infiltration profiling, molecular docking, and molecular dynamics (MD) simulations to investigate the fibrogenic effects of two representative NACs, 1-nitropyrene (1-NP) and nitrobenzene (NB). Identification and evaluation of NACs-related targets and their clinical relevance using the idiopathic pulmonary fibrosis (IPF) GEO dataset.

Network analysis using eight topological algorithms identified ten key genes occupying central positions in the NACs-associated fibrosis-related candidate network. Among these, BCL2L1 and MYC exhibit significant prognostic significance in IPF.Risk models based on hub genes effectively stratify patient survival rates and are closely associated with immune dysregulation, characterized by macrophage aggregation and CD8⁺ T cell exhaustion. Molecular docking analysis indicates that 1-NP and NB exhibit strong binding affinity with the anti-apoptotic protein BCL2L1. Notably, 100-ns MD simulations revealed that NACs binding was associated with significant conformational destabilization and partial unfolding of BCL2L1, as evidenced by sustained increases in Root mean square deviation (RMSD), radius of gyration (Rg), and solvent-accessible surface area (SASA). These findings support a non-classical mechanism of structural toxicity, wherein NACs exert their effects by disrupting protein stability rather than acting as classical enzyme inhibitors.

This study suggests a potential mechanism by which environmental NACs may contribute to fibrotic progression by disrupting the structural stability of BCL2L1 and reshaping the immune microenvironment. Our findings elucidate a potential molecular association between environmental exposure and fibrosis progression, suggesting that BCL2L1-mediated structural toxicity may serve as a potential biomarker and therapeutic target for pollution-related pulmonary fibrosis.