Study reveals mechanism underlying HBV-induced liver inflammation

Chronic hepatitis B virus (HBV) infection remains a major cause of global liver morbidity, leading to progressive necroinflammation that often culminates in cirrhosis and hepatocellular carcinoma. Despite the clinical significance of this chronic inflammatory state, the precise molecular mechanisms that initiate and sustain HBV-induced hepatic damage remain poorly understood.

In a recent Genes & Diseases study, researchers from Chongqing Medical University investigated the mechanisms underlying HBV-induced liver inflammation and identified a reactive oxygen species (ROS)-dependent signaling cascade that activates the Jak2/Stat3 pathway, thereby triggering hepatic inflammatory responses.

Transcriptomic analyses of HBV transgenic mice and liver samples from patients with chronic HBV infection revealed that early hepatic inflammation is characterized by pronounced suppression of mitochondrial oxidative phosphorylation (OXPHOS), particularly genes associated with mitochondrial respiratory complexes I and III, leading to mitochondrial respiratory dysfunction. Functional studies using HBV-replicating hepatocyte cell lines demonstrated that persistent viral replication progressively impaired mitochondrial respiration, resulting in elevated intracellular ROS production. This metabolic disturbance drives excessive accumulation of ROS within the hepatocytes. Similar mitochondrial dysfunction and oxidative stress were observed in HBV replication mouse models during the early stages of liver inflammation, indicating that mitochondrial dysfunction and the resulting ROS accumulation represent initiating events in HBV-associated inflammatory responses.

Mechanistic investigations demonstrated that ROS accumulation activated the antioxidant regulator Nrf2, which subsequently enhanced the production of the pro-inflammatory cytokines IL-6 and IL-8. These cytokines stimulated phosphorylation of Jak2 and Stat3 without altering total protein expression, leading to transcriptional activation of multiple inflammatory genes, including Saa1, S100a9, Icam1, and Socs3, involved in immune cell recruitment and hepatic inflammation. Pharmacological manipulation of ROS levels further confirmed this mechanism, as ROS scavenging with Mito-TEMPO or suppression of HBV replication reduced Nrf2 activation, cytokine production, Jak2/Stat3 signaling, and inflammatory gene expression, whereas ROS induction produced the opposite effects.

This mechanism was further validated in vivo using a pAAV/HBV1.2 mouse model with persistent HBV replication, where increased oxidative stress coincided with elevated Nrf2 expression, enhanced IL-6 and IL-8 production, activation of Jak2/Stat3 signaling, and infiltration of inflammatory cells within the liver. Treatment with the antioxidant N-acetylcysteine (NAC) markedly reduced hepatic ROS accumulation, suppressed activation of the Jak2/Stat3 pathway, decreased inflammatory cytokine expression, and alleviated liver inflammation, demonstrating that oxidative stress is a critical upstream regulator of HBV-induced inflammatory responses.

Collectively, this study establishes mitochondrial dysfunction-induced ROS accumulation as a pivotal trigger of HBV-associated hepatic inflammation through activation of the Nrf2-IL-6/IL-8-Jak2/Stat3 signaling axis. By linking viral replication to oxidative stress and inflammatory signaling, this study provides mechanistic insights into the early pathogenesis of chronic hepatitis B and identifies ROS-dependent Jak2/Stat3 activation as a promising therapeutic target for preventing inflammation-driven liver disease progression.