Abstract

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 (−Gln) 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–glutamine metabolic axis as a promising target, providing novel mechanistic insights and a robust basis for “antioxidant–metabolic” dual-target interventions in early-stage silicosis.

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