p53 deacetylation alleviates calcium oxalate deposition-induced renal fibrosis by inhibiting ferroptosis

• Published in: Biomedicine & pharmacotherapy Vol. 164; p. 114925
• Main Authors: Ye, Zehua, Xia, Yuqi, Li, Lei, Li, Bojun, Chen, Lijia, Yu, Weimin, Ruan, Yuan, Rao, Ting, Zhou, Xiangjun, Cheng, Fan
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.08.2023; Elsevier
• Subjects: Animals; Calcinosis - metabolism; Calcium Oxalate - metabolism; CaOx crystal; Deacetylation; Ferroptosis; Fibrosis; Humans; Kidney - pathology; Kidney Calculi - metabolism; Mice; Oxalates; P53; Renal Insufficiency, Chronic - pathology; Sirtuin 1 - metabolism; Tumor Suppressor Protein p53 - metabolism; Ferroptosis; Deacetylation; CaOx crystal; Fibrosis; P53
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.114925

Calcium oxalate (CaOx) stones are among the most common types of kidney stones and are associated with renal tubular damage, interstitial fibrosis, and chronic kidney disease. The mechanism of CaOx crystal-induced renal fibrosis remains unknown. Ferroptosis, a type of regulated cell death, is characterised by iron-dependent lipid peroxidation, and the tumour suppressor p53 is a key regulator of ferroptosis. In the present study, our results demonstrated that ferroptosis was significantly activated in patients with nephrolithiasis and hyperoxaluric mice as well as verified the protective effects of ferroptosis inhibition on CaOx crystal-induced renal fibrosis. Moreover, the single-cell sequencing database, RNA-sequencing, and western blot analysis revealed that the expression of p53 was increased in patients with chronic kidney disease and the oxalate-stimulated human renal tubular epithelial cell line, HK-2. Additionally, the acetylation of p53 was enhanced by oxalate stimulation in HK-2 cells. Mechanistically, we found that the induction of p53 deacetylation, owing to either the SRT1720-induced activation of deacetylase sirtuin 1 or the triple mutation of p53, inhibited ferroptosis and alleviated renal fibrosis caused by CaOx crystals. We conclude that ferroptosis is one of the critical mechanisms contributing to CaOx crystal-induced renal fibrosis, and the pharmacological induction of ferroptosis via sirtuin 1-mediated p53 deacetylation may be a potential target for preventing renal fibrosis in patients with nephrolithiasis.