Hepatocyte ApoJ accelerates injury-induced liver fibrosis by activation STAT3 through Ranbp2 mediated-SUMOylation

Lamei Liu; Zhaohong Mo; Nong Qin; Jiayi Pi; Linfeng Mao; Ganlu Deng; Minzi Qian; Qiongguang Huang; Shuangdi Duan

doi:10.1016/j.jcmgh.2025.101556

Hepatocyte ApoJ accelerates injury-induced liver fibrosis by activation STAT3 through Ranbp2 mediated-SUMOylation

Cell Mol Gastroenterol Hepatol. 2025 Jun 20:101556. doi: 10.1016/j.jcmgh.2025.101556. Online ahead of print.

Authors

Lamei Liu¹, Zhaohong Mo², Nong Qin³, Jiayi Pi³, Linfeng Mao², Ganlu Deng⁴, Minzi Qian³, Qiongguang Huang², Shuangdi Duan⁵

Affiliations

¹ Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China,530021; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China, 530021; Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China 410082.
² Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China,530021; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China, 530021.
³ Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China 410082.
⁴ Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China,530021; Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China.
⁵ Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China,530021; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China, 530021. Electronic address: shuangdi-go@foxmail.com.

PMID: 40545037
DOI: 10.1016/j.jcmgh.2025.101556

Abstract

Background & aims: Dysregulation of the STAT3 signaling pathway is closely linked to redox homeostasis and exacerbates liver injury. Apolipoprotein J (ApoJ), a chaperone sensitive to redox changes. We aim to investigate how hepatocyte ApoJ regulates the STAT3 pathway to mediate paracrine signaling that activates hepatic stellate cells (HSCs).

Methods: We constructed ApoJ hepatocyte-specific knockout (ApoJ HKO) and overexpression mouse models and induced experimental liver fibrosis. The intercellular signaling between hepatocytes and HSCs was studied by treating HSCs with hepatocyte culture supernatants. Additionally, single-cell RNA sequencing datasets from patients with liver cirrhosis and healthy controls were analyzed.

Results: ApoJ levels in hepatocytes were significantly increased in patients with liver cirrhosis and in several liver fibrosis mouse models. Single-cell RNA analysis revealed that the upregulation of ApoJ primarily occurred in hepatocytes in liver fibrosis subject. ApoJ HKO significantly mitigated liver injury fibrosis models, characterized by reduced HSC activation, F4/80 macrophage infiltration, and maintain redox homeostasis. Conversely, hepatic overexpression of ApoJ aggravated the liver fibrosis phenotype. The underlying mechanism involves oxidative stress-induced ApoJ expression, which in turn enhances SUMOylation of STAT3 in K679 site through interaction with RanBP2. SUMOylation of STAT3 promotes its nuclear translocation, thereby activating the STAT3 pathway, and leads to an increase in TGF-β expression and ROS production in hepatocytes. Administration of the STAT3 inhibitor stattic effectively attenuated the progression of liver fibrosis in mice with hepatic ApoJ overexpression.

Conclusion: ApoJ plays a pivotal role in accelerating the progression of liver fibrosis. Therapeutic strategies targeting the ApoJ/STAT3/RanBP2 axis may offer a novel approach for the prevention and treatment of fibrotic liver diseases.

Keywords: Apolipoprotein J; Liver fibrosis; RanBP2; STAT3; SUMOylation.