{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T12:02:20Z","timestamp":1790596940572,"version":"4.1.0"},"reference-count":96,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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-\u03b2\/Smad (TGF-\u03b2\/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-\u03baB\/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\u2014ranging from antioxidant\/anti-inflammatory agents and TGF-\u03b2\/autophagy modulators to metal chelators and emerging stem cell\/nanomedicine approaches\u2014and 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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1961991","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:40:20Z","timestamp":1790595620000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Research progress on molecular mechanisms and signaling pathways of toxic metal exposure-induced lung fibrosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Dongmei","family":"Zhang","sequence":"first","affiliation":[{"name":"Respiratory Department, First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwen","family":"Liu","sequence":"additional","affiliation":[{"name":"Respiratory Department, First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Yang","sequence":"additional","affiliation":[{"name":"Respiratory Department, First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14235768","article-title":"Epigenetic regulation in chromium-, nickel- and cadmium-induced carcinogenesis","volume":"14","author":"Zhao","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/s00204-024-03903-2","article-title":"Heavy metals: toxicity and human health effects","volume":"99","author":"Jomova","year":"2025","journal-title":"Arch Toxicol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph19158915","article-title":"Inhalation bioaccessibility and risk assessment of metals in PM(2.5) based on a multiple-path particle dosimetry model in the smelting district of Northeast China","volume":"19","author":"Sun","year":"2022","journal-title":"Int J Environ Res Public Health"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/jcdd10110450","article-title":"Contaminant metals and cardiovascular health","volume":"10","author":"Lundin","year":"2023","journal-title":"J Cardiovasc Dev Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/jat.70155","article-title":"Heavy metals and cancer: Unraveling the environmental sources and molecular carcinogenic mechanisms","volume":"46","author":"Rej","year":"2026","journal-title":"J Appl Toxicol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-021-04244-9","article-title":"Involvement of 4-hydroxy-2-nonenal in the pathogenesis of pulmonary fibrosis","volume":"476","author":"Reyes-Jim\u00e9nez","year":"2021","journal-title":"Mol Cell Biochem"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202502689r","article-title":"Metal ion metabolism: The silent catalyst of pulmonary fibrosis","volume":"39","author":"Wan","year":"2025","journal-title":"FASEB J"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtemb.2026.127850","article-title":"The metallic trinity: Understanding the roles and interplay of copper, zinc, and iron in pulmonary fibrosis - 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