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AZD8055 inhibits the secretion of HBV-related antigens through an autophagy-related mechanism

Mengdan Sun^a,b, Yuanyuan Li^a,b, Shaowei Han^a,b, Mingna Hu^a,b,c, Qinghua Zhou^a,b, Jianfeng Lan^a,b,*, Yong Zhang^a,b,*

 
ABSTRACT:     Hepatitis B virus (HBV) affects approximately 300 million people worldwide, leading to chronic liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Despite available treatments like interferon-alpha and nucleoside analogs, these do not eliminate HBV covalently closed circular DNA (cccDNA) from host cells. This study investigates the efficacy of AZD8055, a dual inhibitor of mTORC1 and mTORC2, in reducing HBV antigen secretion in HepG2 and Huh-7 HCC cells. Our findings indicate that AZD8055 significantly decreases both intracellular and extracellular levels of Hepatitis B surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) without compromising cell viability. This inhibition is mediated through the action of AZD8055 on the mTOR pathway, which enhances autophagic activity, a process reversible by autophagy inhibitors: 3-methyladenine (3-MA) and chloroquine (CQ). The results suggest AZD8055 as a potential novel therapeutic approach for HBV, potentially in combination with existing treatments, meriting further clinical investigation to validate these promising preclinical outcomes.

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* Corresponding author, E-mail: jlan200890@163.com, zhangyong@glmc.edu.cn

Received 14 Aug 2024, Accepted 15 Jan 2025