Integrative computational elucidation of molecular mechanisms and multi-target interactions in paraquat-induced pulmonary fibrosis

Paraquat (PQ), a widely used herbicide, induces severe pulmonary fibrosis through complex mechanisms that are not fully understood. This study employed an integrated computational approach combining network toxicology, molecular docking, dynamics simulations, and AlphaFold2-based protein design to systematically investigate PQ-induced pulmonary fibrotic processes. We identified 111 common targets from pulmonary fibrosis and PQ toxicity databases, among which AKT1, IL6, TP53, and CASP3 were recognized as core targets. Functional enrichment analyses revealed significant involvement of oxidative stress, inflammatory response, and apoptotic pathways. Molecular docking demonstrated strong binding affinity between PQ and key targets (docking scores < −5 kcal/mol), while molecular dynamics simulations confirmed stable interactions with favorable binding energies (< −12 kcal/mol). Furthermore, AlphaFold2 predicted three novel proteins exhibiting even higher binding affinity to PQ than natural targets. These findings reveal that PQ might promote pulmonary fibrosis by stably binding to core proteins and activating critical pathological pathways, providing valuable insights for developing targeted biomarkers and therapeutic strategies against PQ-induced lung injury.