Chronic Hepatitis B (CHB) is a prevalent chronic inflammatory liver disease in China, often resulting in sustained hepatic parenchymal damage, liver fibrosis, and adverse outcomes such as cirrhosis, liver failure, and hepatocellular carcinoma (HCC). At the 2024 American Association for the Study of Liver Diseases (AASLD) Annual Meeting, the research team led by Dr. Hong You and Dr. Wei Chen from Beijing Friendship Hospital, Capital Medical University, presented a study analyzing intrahepatic transcriptomic and molecular characteristics in CHB fibrosis patients. Their findings identified a high abundance of proliferative T cell subpopulations (Tpro cells) as a critical factor in fibrosis reversal, offering new potential therapeutic targets for CHB liver fibrosis.
Research Background and Objectives
CHB liver fibrosis is a pathological condition resulting from imbalanced extracellular matrix deposition due to HBV-induced liver damage and repair. This condition can progress to cirrhosis or complications like decompensated cirrhosis and HCC. Evidence indicates that effective antiviral therapy can reverse CHB fibrosis, but some patients fail to achieve reversal, even experiencing disease progression. Clinical studies have shown that fibrosis reversal significantly lowers the risk of liver-related adverse events. This study aimed to uncover the transcriptional and cellular characteristics underlying fibrosis reversal in CHB patients to optimize targeted treatment, stratify prognosis, and enable personalized management.
Methods and Results
The study included 42 CHB fibrosis patients undergoing antiviral therapy, analyzing transcriptomic data from 68 liver biopsy samples. Dynamic transcriptomic comparisons at baseline, 78 weeks, and 260 weeks revealed that fibrosis reversal patients exhibited earlier and faster transcriptomic and molecular reprogramming. Reversal patients initially demonstrated activated immune, proliferative, and profibrotic signals alongside suppressed metabolic signals.
Through orthogonal partial least squares discriminant analysis and functional enrichment analysis, 18 cell cycle-related gene sets, termed CC genes, were identified. Baseline CC gene expression was higher in reversal patients compared to non-reversal patients. In both the discovery group (n=16) and validation group (n=14), baseline CC gene expression levels effectively predicted long-term fibrosis reversal post-antiviral therapy, with area-under-the-curve values of 0.907 and 0.855, respectively.
Public datasets (GSE84044) further categorized 81 CHB fibrosis patients into CClow and CChigh subgroups based on CC gene expression. CChigh patients exhibited transcriptional and molecular characteristics similar to fibrosis reversal patients, suggesting their propensity for fibrosis reversal following antiviral treatment.
Single-cell transcriptomics and multiplex immunofluorescence identified a novel proliferative CD8+ T cell subset (Tpro cells) as the primary source of CC gene expression. Tpro cells demonstrated robust proliferative capacity (CChigh), tissue-resident memory (ITGAEhighCD44+CD69+), and cytotoxicity (GZMAhigh GZMBhigh IFNGhigh PRF1high TCF7low PDCD1low). CHB fibrosis patients with higher baseline Tpro cell frequency were less likely to achieve low viral load during treatment but showed greater potential for fibrosis reversal.
Conclusions
Fibrosis reversal in CHB patients is associated with high baseline immune, proliferative, and profibrotic activity alongside suppressed metabolic function. Elevated CC gene expression and Tpro cell abundance at baseline predict early and robust transcriptomic recovery, with a lower likelihood of low viral load during treatment. These findings provide a foundation for early identification, treatment monitoring, and management of CHB fibrosis patients unlikely to achieve reversal.
