Wei Chen, Zeyan Xu, Jingjing Jiang, Wen Feng, Baiwen Li
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引用次数: 0
Abstract
The pathogenesis of Crohn's disease (CD) remains unclear, with mitochondrial dysfunction and ferroptosis emerging as important contributors. However, the specific mechanisms linking mitochondria, ferroptosis, and CD are not well understood. Through bioinformatics analysis using the Gene Expression Omnibus database, AFG3L2 was identified as a key mitochondrial gene and subjected to functional enrichment and immune infiltration analyses. Lipopolysaccharide-induced NCM460 cells were used in vitro. Overexpression of AFG3L2 inhibited the release of inflammatory factors, enhanced antioxidant capacity, and reduced reactive oxygen species production. In addition, AFG3L2 overexpression activated the peroxisome proliferator-activated receptor-A (PPARA) signaling pathway and promoted the nuclear translocation of PPARA. As a downstream target of PPARA, glutathione peroxidase 4 (GPX4) transcriptional activity was regulated by PPARA. AFG3L2 facilitated the binding of PPARA to the GPX4 promoter region, thereby enhancing GPX4 transcription. Importantly, the regulation of GPX4 by AFG3L2 was dependent on the activation of PPARA. 2,4,6-Trinitrobenzenesulfonic acid-induced colitis in mice was used as an in vivo model. Overexpression of AFG3L2 preserved mitochondrial ultrastructure, suppressed intestinal inflammation, and promoted the expression of PPARA and GPX4. In summary, the results of this study reveal the protective role of the AFG3L2/PPARA/GPX4 axis in maintaining intestinal mucosal integrity and suggest it as a potential therapeutic target for CD.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.