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.

Objective To explore the relationship between traditional Chinese medicine (TCM) syndromes of state of evil domination and clinical and laboratory indicators of IgA nephropathy. Methods A prospective study was used to collect data on clinical and laboratory examination of IgA nephropathy in multi clinical centers. Patients’ TCM syndrome types were determined according to the national diagnostic criteria at the same time. Totally 266 patients with IgA nephropathy were included in the study to establish a database for analyzing the relationship between TCM syndrome of state of evil domination and clinical and laboratory indicators. Results In the relationship between syndromes of state of evil domination distribution and clinical subtypes, patients of wind-heat syndrome had more macroscopic hematuria;patients of phlegm-damp syndrome had more nephrotic syndrome;patients of damp-heat syndrome had more chronic nephritis type Ⅰ;patients of blood stasis syndrome had more chronic nephritis type Ⅱ. In the relationship between syndrome of state of evil domination distribution and clinical manifestation, the incidence of hypertension was higher in patients of blood stasis syndrome than in other three types. It was more serious for hematuresis in the patients of wind-heat syndrome. For patients of phlegm-damp syndrome, the incidence of heave proteinuria was highest. In the relationship between syndrome of state of evil domination distribution and laboratory examination, 24-hour urinary protein quantification was higher than in patients of wind-heat and damp-heat syndrome, but the level of blood albumin was lowest. For patients of blood stasis syndrome, serum creatinine level was significantly higher than in other three types;the level of eGFR was just the opposite. The levels of blood cholesterol and triglyceride in patients of phlegm-damp syndrome were higher than in other three types. The activated partial thromboplastin time (APTT) levels in patients of blood stasis and phlegm-damp syndrome were lower than in other patients, but the FIB level was the exact opposite of APTT. In the relationship between syndrome of state of evil domination distribution and the stages of chronic kidney disease (CKD), patients of wind-heat syndrome were more in the first stage of CKD;patients of blood stasis syndrome were more in the third stage of CKD. Conclusion There is relative correlation between TCM syndromes of state of evil domination and clinical and laboratory indicators in IgA nephropathy, which would provide some reference to narrow the gap in the information of the four methods of TCM with clinical and laboratory indicators to enhance accurate diagnosis of TCM syndrome.