WOFAPS 2025 8th World Congress of Pediatric Surgery

Shuhao Zhang, Qingjiang Chen, Zhigang Gao

Children's Hospital Zhejiang University School of Medicine, Hangzhou, China

Background: Recurrent liver inflammation is a major contributor to the liver fibrosis and cirrhosis. We aim to identify novel pharmacological targets to mitigate recurrent liver inflammation and provide novel strategies for treating pediatric hepatobiliary disorders.

Methods: A rat model of cholestasis was established by common bile duct ligation, and in vitro experiments were conducted by stimulating HHL-5 hepatocytes or MCL-1 knockout HHL-5 hepatocytes with glycochenodeoxycholate. Following intervention with UMI-77, inflammatory factor secretion was measured in rat serum and hepatocyte culture supernatant using ELISA. Immunofluorescence and electron microscopy were performed to observe mitophagy. HE staining was used to assess liver fibrosis. Mitophagy-related protein expression levels were analyzed via Western blotting.

Results: In the experimental group, histological analysis showed that the majority of rats still retained a normal hepatic lobular structure, with clearly visible central veins. The secretion levels of NF-κB and IL-6 in the rat serum and hepatocyte culture medium were significantly reduced compared to the control group. Western blotting analysis revealed increased expression of the mitophagy-related proteins MCL-1 and LC3A, along with decreased expression of TOM20 and TIM23 in rat liver tissue and hepatocytes. Immunofluorescence indicated an increased number of hepatocytes lysosomes and electron microscopy showed a higher number of autophagosomes. However, in the MCL-1 knockout hepatocytes, no suppression of NF-κB and IL-6 secretion levels was observed.

Conclusions: Induction of mitophagy in cholestatic liver alleviates inflammatory damage and delays disease progression. MCL-1-mediated mitophagy holds promise as a potential therapeutic strategy for managing inflammatory liver injury in pediatric hepatobiliary diseases.