Chronic hepatitis B virus infection continues to be a significant cause of liver disease worldwide, leading to progressive necroinflammation that can result in cirrhosis and hepatocellular carcinoma, according to a Jul. 17 study from Chongqing Medical University.
The research team investigated the molecular mechanisms underlying HBV-induced liver inflammation and identified a reactive oxygen species (ROS)-dependent signaling cascade that activates the Jak2/Stat3 pathway, triggering hepatic inflammatory responses. Transcriptomic analyses of HBV transgenic mice and samples from patients with chronic HBV infection showed early hepatic inflammation is marked by suppression of mitochondrial oxidative phosphorylation, particularly affecting genes related to mitochondrial respiratory complexes I and III. This leads to mitochondrial respiratory dysfunction.
Functional studies using HBV-replicating hepatocyte cell lines found that persistent viral replication impairs mitochondrial respiration over time, resulting in increased intracellular ROS production. The accumulation of ROS within hepatocytes was also observed in mouse models during early stages of liver inflammation, suggesting that mitochondrial dysfunction and subsequent ROS buildup are initiating events in HBV-associated inflammatory responses.
Mechanistic investigations revealed that the accumulation of ROS activates the antioxidant regulator Nrf2, which increases production of pro-inflammatory cytokines IL-6 and IL-8. These cytokines then stimulate phosphorylation of Jak2 and Stat3 without changing total protein expression levels, leading to transcriptional activation of multiple inflammatory genes involved in immune cell recruitment and hepatic inflammation. Pharmacological manipulation confirmed this mechanism: scavenging ROS or suppressing HBV replication reduced Nrf2 activation, cytokine production, Jak2/Stat3 signaling, and inflammatory gene expression, while inducing ROS had opposite effects.
The mechanism was further validated using an animal model with persistent HBV replication where increased oxidative stress coincided with higher Nrf2 expression, elevated IL-6 and IL-8 levels, activation of Jak2/Stat3 signaling, and infiltration of inflammatory cells within the liver. Treatment with an antioxidant reduced hepatic ROS accumulation as well as markers associated with inflammation.
The study concludes that mitochondrial dysfunction-induced ROS accumulation is a key trigger for HBV-associated hepatic inflammation through activation of the Nrf2-IL-6/IL-8-Jak2/Stat3 axis. The findings provide insight into early pathogenesis mechanisms for chronic hepatitis B and suggest potential therapeutic targets for preventing progression driven by inflammation.
