Hepatocyte Apolipoprotein J Accelerates Injury-induced Liver Fibrosis by Activation Signal Transducer and Activator of Transcription 3 Through Ranbp2 Mediated-SUMOylation

BACKGROUND & AIMS: Dysregulation of the signal transducer and activator of transcription 3 (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 subjects. ApoJ HKO significantly mitigated liver injury fibrosis models, characterized by reduced HSC activation, F4/80 macrophage infiltration, and maintained 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 transforming growth factor-β expression and reactive oxygen species production in hepatocytes. Administration of the STAT3 inhibitor stattic effectively attenuated the progression of liver fibrosis in mice with hepatic ApoJ overexpression. CONCLUSIONS: 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.