Unveiling the role of Pafah1b3 in liver fibrosis: A novel mechanism revealed.
10.1016/j.jpha.2024.101158
- Author:
Lifan LIN
1
;
Shouzhang YANG
2
;
Xinmiao LI
1
;
Weizhi ZHANG
1
;
Jianjian ZHENG
1
Author Information
1. Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
2. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
- Publication Type:Journal Article
- Keywords:
Hepatic stellate cells;
Liver fibrosis;
Platelet-activating factor acetylhydrolase 1B3;
Transforming growth factor-β signaling;
Ubiquitination
- From:
Journal of Pharmaceutical Analysis
2025;15(1):101158-101158
- CountryChina
- Language:English
-
Abstract:
Liver fibrosis is a common outcome of various chronic hepatic insults, characterized by excessive extracellular matrix (ECM) deposition. The precise mechanisms, however, remain largely undefined. This study identified an elevated expression of platelet-activating factor acetylhydrolase 1B3 (Pafah1b3) in liver tissues from both carbon tetrachloride (CCl4)-treated mice and patients with cirrhosis. Deletion of Pafah1b3 significantly attenuated CCl4-induced fibrosis, hepatic stellate cell (HSC) activation, and activation of transforming growth factor-β (TGF-β) signaling. Mechanistically, PAFAH1B3 binds to mothers against decapentaplegic homolog 7 (SMAD7), disrupting SMAD7's interaction with TGF-β receptor 1 (TβR1), which subsequently decreases TβR1 ubiquitination and degradation. Pharmacological inhibition using 3-IN-P11, a specific Pafah1b3 inhibitor, conferred protective effects against CCl4-induced fibrosis in mice. Furthermore, Pafah1b3 deficiency reduced hepatic inflammation. Overall, these results establish a pivotal role for Pafah1b3 in modulating TGF-β signaling and driving HSC activation.
