TY  - JOUR
AU  - Song, Rui
AU  - Yu, Shasha
AU  - Chen, Xueyan
AU  - Ling, Ning
AU  - Cai, Dachuan
AU  - Ren, Hong
AU  - Chen, Min
PY  - 2026
TI  - Activation of the Jak2/Stat3 pathway by ROS-dependent signaling cascades initiates hepatitis B virus-induced hepatic inflammatory responses
JO  - Genes & Diseases
SN  - 2352-4820
VL  - 13
IS  - 5
AB  - Chronic liver necroinflammation induced by hepatitis B virus (HBV) infection plays a major causative role in the development of end-stage liver diseases; however, mechanisms contributing to its initiation remain unclear. Analysis of the hepatic transcriptome from HBV-replication mice or HBV-infected patients revealed that significantly down-regulated mitochondrial oxidative phosphorylation function was the salient transcriptional feature at the early stage of liver inflammation compared with the stage without liver inflammation. In cell models, persistent HBV replication-induced progressive impairment of mitochondrial respiration resulted in increased reactive oxygen species (ROS) levels. We further discovered that HBV replication-induced ROS accumulation was essential for the up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2)-associated interleukin (IL)-6/IL-8 production, mediating the activation of Janus kinase 2 (Jak2)/signal transducer and activator of transcription (Stat3) signaling, and then the expression of downstream inflammatory genes. These observations were also identified in HBV-replication mice at the early stage of liver inflammation, which exhibited elevated hepatic oxidative stress, Nrf2 expression, IL-6 and IL-8 production, and Jak2/Stat3 activation, alongside hepatic inflammatory cell infiltration. In vivo, ROS scavenging with N-acetylcysteine (NAC) mitigated these effects. Our findings underscore the critical role of ROS-dependent Jak2/Stat3 pathway activation in the occurrence of HBV-induced liver inflammation, providing new insights into the pathogenesis of chronic hepatitis B.
UR  - https://doi.org/10.1016/j.gendis.2025.101857
DO  - 10.1016/j.gendis.2025.101857