IRF1/ZNF350/GPX4-mediated ferroptosis of renal tubular epithelial cells promote chronic renal allograft interstitial fibrosis.

Renal interstitial fibrosis and tubular atrophy are essential pathological characteristics of chronic renal allograft dysfunction (CAD). Herein, we revealed that ferroptosis of renal tubular epithelial cells (RTECs) might contribute to renal tubular injury in CAD. Mechanistically, TNF-α induced ferroptosis by inhibiting GPX4 transcription through upregulating IRF1 in RTECs. IRF1 could bind with ZNF350 to form a transcription factor complex, which directly binds to the GPX4 promoter region to inhibit GPX4 transcription. Ferroptotic RTECs might secrete profibrotic factors, including PDGF-BB and IL-6, to activate neighboring fibroblasts to transform into myofibroblasts or induce EMT in adjacent RTECs. In conclusion, our results confirmed a novel role of ferroptosis in renal tubular injury and interstitial fibrosis, thereby providing insights into the pathogenesis of chronic renal allograft interstitial fibrosis during CAD. Copyright © 2022. Published by Elsevier Inc.

Citation

Yao Zhang, Jianjian Zhang, Dengyuan Feng, Hai Zhou, Zeping Gui, Ming Zheng, Zhou Hang, Zijie Wang, Zengjun Wang, Min Gu, Ruoyun Tan. IRF1/ZNF350/GPX4-mediated ferroptosis of renal tubular epithelial cells promote chronic renal allograft interstitial fibrosis. Free radical biology & medicine. 2022 Nov 20;193(Pt 2):579-594

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PMID: 36356714

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