Deubiquitinase OTUD6A alleviates acetaminophen-induced liver injury by targeting EZH2 to reduce cell death in hepatocytes.

Yanni ZHAO; Tianyang JIN; Tingxin XU; Yi FANG; Qingsong ZHENG; Wu LUO; Weiwei ZHU; Yue CHEN; Jiong WANG; Yi CHEN; Wei ZUO; Lijiang HUANG; Guang LIANG; Yi WANG

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Deubiquitinase OTUD6A alleviates acetaminophen-induced liver injury by targeting EZH2 to reduce cell death in hepatocytes.

Author: Yanni ZHAO ¹ ; Tianyang JIN ² ; Tingxin XU ² ; Yi FANG ² ; Qingsong ZHENG ² ; Wu LUO ² ; Weiwei ZHU ¹ ; Yue CHEN ² ; Jiong WANG ² ; Yi CHEN ² ; Wei ZUO ³ ; Lijiang HUANG ³ ; Guang LIANG ¹ ; Yi WANG ¹
Author Information

1. Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou 325000, China.
2. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
3. Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo 315700, China.
Publication Type:Journal Article
Keywords: Acetaminophen; Cell death; Deubiquitinating enzyme; ER stress; EZH2; Liver injury; OTUD6A; OUT family
From: Acta Pharmaceutica Sinica B 2025;15(9):4772-4788
CountryChina
Language:English
Abstract: Acetaminophen (APAP) is the primary cause of drug-induced acute liver failure. Ovarian tumor deubiquitinase 6A (OTUD6A), a recently discovered deubiquitinase of the OTU family, has been primarily studied in tumor contexts. However, its role in APAP-induced liver injury (AILI) remains unclear. Therefore, this study aimed to investigate the involvement of OTUD6A in the pathogenesis of AILI. Our findings demonstrated a substantial upregulation of OTUD6A in both the liver tissue and isolated hepatocytes of mice following APAP stimulation. OTUD6A knockout exacerbated APAP-induced inflammation, hepatocyte necrosis, and liver injury, whereas OTUD6A overexpression alleviated these pathologies. Mechanistically, OTUD6A directly interacted with the enhancer of zeste homolog 2 (EZH2) and selectively removed K48-linked polyubiquitin chains from EZH2, enhancing its stability. This resulted in increased protein levels of EZH2 and H3K27me3, as well as reduced endoplasmic reticulum (ER) stress and cell death in hepatocytes. Collectively, our research uncovers a novel role for OTUD6A in mitigating APAP-induced liver injury by promoting EZH2 stabilization.