The SOX4/EZH2/SLC7A11 signaling axis mediates ferroptosis in calcium oxalate crystal deposition-induced kidney injury

• Published in: Journal of translational medicine Vol. 22; no. 1; p. 9
• Main Authors: Yan, Xinzhou, Xia, Yuqi, Li, Bojun, Ye, Zehua, Li, Lei, Yuan, Tianhui, Song, Baofeng, Yu, Weimin, Rao, Ting, Ning, Jinzhuo, Lin, Fangyou, Mei, Shuqin, Mao, Zhiguo, Zhou, Xiangjun, Li, Wei, Cheng, Fan
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 02.01.2024; BioMed Central; BMC
• Subjects: Amino Acid Transport System y; Analysis; Animals; Antibodies; Calcium Oxalate; Calculi; Care and treatment; Cell death; Chromatin; Chronic kidney failure; Demographic aspects; Diabetes; Diabetes mellitus; Diabetic nephropathies; Diabetic Nephropathies - metabolism; Diagnosis; DNA methylation; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; EZH2; Ferroptosis; Fibrosis; Health aspects; Histone H3; Histones; Histones - metabolism; Humans; Immunoprecipitation; Kidney - pathology; Kidney Calculi - pathology; Kidney diseases; Kidney injury; Kidney stones; Kidneys; Laboratory animals; Lupus; Lupus nephritis; Medical research; Methylation; Mice; Nephrolithiasis; Nephropathy; Oxalates; Oxalic acid; Pathogenesis; Prevention; Renal cell carcinoma; Ribonucleic acid; Risk factors; RNA; RNA - metabolism; SOX4; SOXC Transcription Factors - metabolism; Western blotting; China; Beijing China; United States > US; Ferroptosis; Kidney injury; SOX4; EZH2; Kidney stones
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-023-04793-1

Epigenetic regulation is reported to play a significant role in the pathogenesis of various kidney diseases, including renal cell carcinoma, acute kidney injury, renal fibrosis, diabetic nephropathy, and lupus nephritis. However, the role of epigenetic regulation in calcium oxalate (CaOx) crystal deposition-induced kidney injury remains unclear. Our study demonstrated that the upregulation of enhancer of zeste homolog 2 (EZH2)-mediated ferroptosis facilitates CaOx-induced kidney injury. CaOx crystal deposition promoted ferroptosis in vivo and in vitro. Usage of liproxstatin-1 (Lip-1), a ferroptosis inhibitor, mitigated CaOx-induced kidney damage. Single-nucleus RNA-sequencing, RNA-sequencing, immunohistochemical and western blotting analyses revealed that EZH2 was upregulated in kidney stone patients, kidney stone mice, and oxalate-stimulated HK-2 cells. Experiments involving in vivo EZH2 knockout, in vitro EZH2 knockdown, and in vivo GSK-126 (an EZH2 inhibitor) treatment confirmed the protective effects of EZH2 inhibition on kidney injury and ferroptosis. Mechanistically, the results of RNA-sequencing and chromatin immunoprecipitation assays demonstrated that EZH2 regulates ferroptosis by suppressing solute carrier family 7, member 11 (SLC7A11) expression through trimethylation of histone H3 lysine 27 (H3K27me3) modification. Additionally, SOX4 regulated ferroptosis by directly modulating EZH2 expression. Thus, this study demonstrated that SOX4 facilitates ferroptosis in CaOx-induced kidney injury through EZH2/H3K27me3-mediated suppression of SLC7A11.