{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:28:35Z","timestamp":1785421715295,"version":"3.56.0"},"reference-count":54,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82374266"],"award-info":[{"award-number":["82374266"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82374266"],"award-info":[{"award-number":["82374266"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"crossref","award":["2025JJ90015"],"award-info":[{"award-number":["2025JJ90015"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"crossref","award":["2026JJ60555"],"award-info":[{"award-number":["2026JJ60555"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Scientific Research Project of Hunan Provincial Health Commission","award":["20254596"],"award-info":[{"award-number":["20254596"]}]},{"name":"Hunan Provincial Innovation Training Program for College Students","award":["S202510541099"],"award-info":[{"award-number":["S202510541099"]}]},{"name":"Undergraduate Research and Innovation Project of Hunan University of Chinese Medicine","award":["2024BKS088"],"award-info":[{"award-number":["2024BKS088"]}]},{"name":"Undergraduate Research and Innovation Project of Hunan University of Chinese Medicine","award":["2025BKS143"],"award-info":[{"award-number":["2025BKS143"]}]},{"award":["2024BKS088"],"award-info":[{"award-number":["2024BKS088"]}],"id":[{"id":"https:\/\/ror.org\/05htk5m33","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2025BKS143"],"award-info":[{"award-number":["2025BKS143"]}],"id":[{"id":"https:\/\/ror.org\/05htk5m33","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>As a major occupational hazard, crystalline silica (SiO2) poses a severe risk of pulmonary toxicity. While the irreversible fibrosis of late-stage silicosis has been extensively studied, the cellular and molecular mechanisms by which SiO2 reprograms macrophage metabolism to drive early pathogenesis remain poorly understood. To elucidate this early immune-inflammatory response, we combined targeted metabolomics, pharmacological treatments, and nutrient deprivation in murine alveolar macrophages. Our results demonstrate that SiO2 exposure severely impairs the master antioxidant regulator, nuclear factor erythroid 2-related factor 2 (Nrf2), triggering excessive reactive oxygen species (ROS) accumulation and upregulated glutamine catabolism to drive pro-inflammatory M1 macrophage polarization. We demonstrated that Nrf2 activation with tert-butylhydroquinone (TBHQ) redirected glutamine metabolic flux from pro-inflammatory catabolism to antioxidant anabolism, significantly attenuating SiO2-induced M1 polarization. Conversely, Nrf2 inhibition via ML385 exacerbated the inflammatory response. Furthermore, introducing a glutamine deprivation (\u2212Gln) model revealed that restricting glutamine availability significantly attenuated the ability of Nrf2 to reverse M1 polarization, suggesting that its immune-protective effects largely depend on an intact glutamine metabolic pathway. Ultimately, our findings underscore the severe risks of silica exposure and identify the Nrf2\u2013glutamine metabolic axis as a promising target, providing novel mechanistic insights and a robust basis for \u201cantioxidant\u2013metabolic\u201d dual-target interventions in early-stage silicosis.<\/jats:p>","DOI":"10.3390\/toxics14070602","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T11:43:34Z","timestamp":1783683814000},"page":"602","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nrf2 Activation Alleviates Silica-Induced Toxicity in Alveolar Macrophages via Glutamine Metabolic Reprogramming"],"prefix":"10.3390","volume":"14","author":[{"given":"Xinyi","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Preventive Medicine, School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jixia","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangguo","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pathogenic Biology, School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine, School of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0283-7716","authenticated-orcid":false,"given":"Jun","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, School of Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Liu, X., Jiang, Q., Wu, P., Han, L., and Zhou, P. 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