Research progress on molecular mechanisms and signaling pathways of toxic metal exposure-induced lung fibrosis

Abstract

Toxic metal exposure is a pressing global health concern, with accumulating evidence linking it to the onset and progression of pulmonary fibrosis. Mechanistically, metal-induced pulmonary fibrosis operates through a complex, interconnected signaling network rather than a single linear cascade. The initiating role of oxidative stress and the central hub function of the transforming growth factor-β/Smad (TGF-β/Smad) pathway are well-established, whereas the contributions of non-canonical mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and mammalian target of rapamycin complex 1 (mTORC1) pathways are supported by varying degrees of preclinical evidence, with some crosstalk mechanisms remaining largely hypothetical. Concurrently, persistent Toll-like receptor 4/nuclear factor kappa-B/NOD-like receptor family pyrin domain containing 3 (TLR4/NF-κB/NLRP3)-driven inflammation, macrophage polarization imbalance, impaired autophagy-lysosomal function, and non-apoptotic cell death pathways including ferroptosis and pyroptosis collectively promote alveolar epithelial injury, fibroblast-to-myofibroblast transition, and excessive extracellular matrix deposition. We summarize current therapeutic strategies—ranging from antioxidant/anti-inflammatory agents and TGF-β/autophagy modulators to metal chelators and emerging stem cell/nanomedicine approaches—and highlight their preclinical promise and translational challenges. Major unresolved issues include the translational gap between animal models and real-world human exposure scenarios, controversies over mixed-metal dose-response thresholds, and insufficient understanding of feedback and compensatory mechanisms within the molecular network. We outline future research directions aimed at bridging these gaps, with the goal of establishing a comprehensive theoretical framework for early warning, precision diagnosis, and targeted intervention in toxic metal-related pulmonary fibrosis.