image: (A) OCR was measured by Seahorse analyzer to determine basal respiration, ATP-linked respiration, proton leak, and maximal respiration capacity in HepG2 and HBV-replication hepatoma cell lines (HepG2.2.15 and HepAD38) with or without antiviral agent (ETV) treatment. (B) MMP was detected using JC-1 dye by flow cytometry in HepG2, HepG2.2.15, and HepAD38 with or without ETV treatment. A decrease in the JC-1 aggregates/monomers ratio indicated declined MMP, mitochondrial depolarization, or mitochondrial dysfunction. (C–E) Intracellular ATP levels and mitochondrial complex Ⅰ or Ⅲ activity were assayed in HepG2, HepG2.2.15, and HepAD38 with or without ETV treatment. (F) Cellular ROS levels were determined using DCFH-DA dye by flow cytometry in HepG2, HepG2.2.15, and HepAD38 with or without ETV treatment. Higher MFI of DCFH-DA dye indicated more ROS production in cells. (G) Cellular ROS levels were detected using DCFH-DA dye by flow cytometry in HepG2, HepG2.2.15, and HepAD38 cells with or without treatment of mitochondria-targeted ROS scavenger Mito-TEMPO after 24, 48, and 72 h of incubation period. All data were shown as mean ± standard error of the mean from at least 3 independent experiments. P-values < 0.05 were considered statistically significant (∗P < 0.05, ∗∗P < 0.01, or ∗∗∗P < 0.001 between two indicated groups). OCR, oxygen consumption rate; ETV, entecavir; MMP, mitochondrial membrane potential; ATP, adenosine triphosphate; ROS, reactive oxygen species; MFI, mean fluorescence intensity; HBV, hepatitis B virus.
Credit: Rui Song, Shasha Yu, Xueyan Chen, Ning Ling, Dachuan Cai, Hong Ren, Min Chen
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.
Reference
Title of the original paper: Activation of the Jak2/Stat3 pathway by ROS-dependent signaling cascades initiates hepatitis B virus-induced hepatic inflammatory responses
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101857
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