20-Hydroxyeicosatetraenoic Acid Ameliorates Nickel Nanoparticle-Induced Epithelial-Mesenchymal Transition by Modulating the FFAR1/NF-kB Pathway

  • Chem Res Toxicol. 2026 Jul 20;39(7):1320-1333. doi: 10.1021/acs.chemrestox.6c00048.
Jiali Yuan  1  2 ,  Huihui Yang  1  2 ,  Shuai Zhang  1  2 ,  Zhenyu Yan  1  2 ,  Jing Li  1  2 ,  Yiqun Mo  3 ,  Qunwei Zhang  3 ,  Zhenyao Huang  1  2
Affiliations
  • 1. Key Laboratory of Human Genetics and Environmental Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
  • 2. School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
  • 3. Department of Epidemiology and Population Health, University of Louisville, Louisville, Kentucky 40202, United States.
PMID: 42315976 DOI: 10.1021/acs.chemrestox.6c00048
Abstract

Nickel nanoparticles (Nano-Ni) are widely utilized in industrial and biomedical applications due to their unique physicochemical properties. However, their expanded usage increases risks of occupational and environmental exposure. In this study, we established a mouse exposure model via single intratracheal instillation of Nano-Ni and analyzed the perturbation characteristics of lung tissue metabolic profiles using untargeted metabolomics. Subsequently, the biological function of the key metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) was explored in Nano-Ni-exposed lung epithelial cells to elucidate the underlying mechanisms of metabolic alterations in Nano-Ni-induced pulmonary fibrosis. Our results showed that exposure to Nano-Ni induced marked alveolar architecture destruction, interstitial thickening, and upregulated expression of fibrotic markers in mouse lung tissues. Metabolomics identified arachidonic acid metabolism as the most disrupted pathway, with 20-HETE exhibiting the most pronounced downregulation. In both BEAS-2B and A549 cell lines, exogenous 20-HETE supplementation significantly attenuated Nano-Ni-induced epithelial-mesenchymal transition (EMT). Furthermore, Nano-Ni exposure reduced mRNA and protein levels of Free Fatty Acid Receptor 1 (FFAR1) both in vivo and in vitro. Pretreatment with the FFAR1 agonist GW9508 mitigated Nano-Ni-induced EMT and the activation of NF-κB signaling pathway in both cell lines. Critically, FFAR1 inhibition largely abolished the suppressive effects of 20-HETE on EMT and NF-κB signaling. Altogether, our study suggests that 20-HETE may affect the EMT process in lung epithelial cells at least in part through regulating the FFAR1/NF-κB pathway, thereby potentially contributing to the process of Nano-Ni-induced lung fibrosis. These findings point to a possible role of specific metabolites in Nano-Ni-induced pulmonary fibrosis and may provide novel mechanistic insights into the inhalation toxicity of nanomaterials.

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