This new study published in Genes & Diseases by researchers from Children's Hospital of Chongqing Medical University and Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering identifies selenoprotein glutathione peroxidase 3 (GPX3) as a critical endogenous protector against renal IRI. Using both in vivo rat models and in vitro hypoxia–reoxygenation systems, the researchers demonstrate that GPX3 plays a central role in limiting inflammation, oxidative damage, and renal dysfunction following ischemic insult.

The researchers show that renal IRI leads to a pronounced reduction in GPX3 expression, coinciding with impaired renal function, tubular structural damage, increased apoptosis, and heightened inflammatory cytokine production. Restoring GPX3 expression through viral overexpression markedly improved renal functional indices, reduced histopathological injury, and alleviated tubular epithelial cell death. These findings establish GPX3 as an essential determinant of renal resilience during ischemia–reperfusion stress.

Mechanistic analyses revealed that GPX3 exerts its protective effects by suppressing activation of the mitogen-activated protein kinase (MAPK) signaling pathway, a key mediator of inflammatory amplification in AKI. Renal IRI was associated with robust MAPK activation and increased expression of pro-inflammatory mediators, whereas GPX3 overexpression significantly attenuated MAPK signaling and downstream inflammatory responses.

In addition, the researchers identify NADPH oxidase (NOX) as a critical downstream effector of GPX3-mediated protection. IRI-induced upregulation of NOX enzymes resulted in excessive reactive oxygen species production, exacerbating oxidative stress and inflammation. GPX3 markedly reduced NOX expression and ROS accumulation, thereby dampening oxidative injury. Importantly, pharmacological activation of MAPK signaling reversed the anti-inflammatory and antioxidant effects of GPX3, confirming that GPX3 functions through a MAPK–NOX regulatory axis.

Cell-based experiments further corroborated these findings, showing that GPX3 overexpression reduced hypoxia–reoxygenation–induced apoptosis and inflammatory cytokine release in renal tubular epithelial cells, while enhancing the expression of anti-inflammatory mediators.

Together, these results identify GPX3 as a key endogenous regulator of inflammatory and oxidative stress pathways in renal ischemia–reperfusion injury. By linking GPX3 to suppression of MAPK signaling and NADPH oxidase activity, this study provides new mechanistic insight into AKI pathogenesis and highlights GPX3 as a promising therapeutic target for preventing or mitigating renal injury in ischemic conditions.

Reference

Title of Original Paper
Selenoprotein GPX3 regulates NADPH oxidase expression by inhibiting the MAPK signaling pathway and thereby attenuating the inflammatory response in renal ischemia-reperfusion injury

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101640

Funding Information:

• The Chongqing Natural Science Foundation Innovation and Development Joint Fund Project (China) (No. CSTB2024NSCQ-LZX0072)
• The Program for Youth Innovation in Future Medicine, Chongqing Medical University (China) (No. W0201)
• The Joint Medical Research Project of Chongqing Science and Technology Bureau and Health Commission (China) (No. 2024MSXM002)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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