OTUD7B attenuates renal fibrosis by regulating PRDX1 protein stability.

INTRODUCTION Renal fibrosis as a common pathological endpoint in chronic kidney disease (CKD) and end-stage renal disease (ESRD) is a serious threat to patients' life and health. In recent years, the link between epigenetic modifications and renal fibrosis has been increasingly discovered.

OBJECTIVES This study aimed to investigate the effects of the deubiquitinating enzyme OTUD7B on renal fibrosis and its underlying mechanism.

METHODS Transcriptome sequencing of control and fibrotic cells were performed to screen for deubiquitinating enzymes, and the expression of these enzymes were validated in cellular models, animal models, and clinical specimens. The specific role of OTUD7B in renal fibrosis was elucidated through knockdown and overexpression experiments. Subsequently, IP-MS was employed to identify OTUD7B downstream targets, confirming its interaction with PRDX1 and detecting PRDX1 ubiquitination levels and sites. Finally, IP and UbiBrowser were used to predicte SMURF1 as the PRDX1 ubiquitin ligase. Detection of ubiquitination levels and sites revealed that OTUD7B and SMURF1 maintained PRDX1 protein stability together.

RESULTS The reduction of renal fibrosis deubiquitinating enzyme, OTUD7B, was identified by RNA sequencing and validated in cellular, animal and human samples. In addition, its function was verified by knockdown and overexpression of OTUD7B, with overexpression attenuating renal fibrosis and knockdown exacerbating it. Mechanistically, through reducing SMURF1-mediated K63-linked ubiquitination and subsequent lysosomal degradation of PRDX1, OTUD7B elevated PRDX1 expression, resulting in attenuation of renal fibrosis.

CONCLUSION Collectively, targeting the OTUD7B-SMURF1-PRDX1 axis may offer a promising therapeutic approach for renal fibrosis.