Targeting Ferroptosis Restores the Antiviral Activity of CD8+ T Cells During Chronic Hepatitis B Virus Infection

作者：Haohao Li, Su Xiao, C.Y. Huo, Shasha Yang, Jun Wang, Xin Lan, Meng-Hua Li, Lizhi Shi, Zhuo Li, Jian Zhang, Huajun Zhao, Qiuju Han · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2025 · DOI：10.1016/j.jcmgh.2025.101612 · 被引用次数：6 · 研究领域：Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers、Epigenetics and DNA Methylation

Background & Aims CD8 + T cells play a crucial role in antiviral immunity; however, hepatitis B virus (HBV)-specific CD8 + T cells become dysfunctional during chronic HBV (CHB) infection. Blocking inhibitory pathways only partially restores efficient antiviral responses, suggesting that the mechanism underlying CD8 + T-cell dysfunction is complicated. This study aimed to investigate whether HBV-specific CD8 + T cells undergo ferroptosis, examine its correlation with T-cell dysfunction, and elucidate the underlying mechanism and potential intervention strategies. Methods Analysis of CD8 + T cells from patients with CHB revealed ferroptosis markers via flow cytometry, electron microscopy, and single-cell RNA sequencing, and HBV-specific CD8 + T cells were identified using HBV-core antigen peptide-loaded major histocompatibility complex I tetramer. Flow cytometry, single-cell RNA sequencing, and additional experimental approaches were employed to investigate the ferroptosis-associated mechanisms in CD8 + T-cell dysfunction. Results Ferroptosis was observed in CD8 + T cells from patients with CHB, as indicated with increased lipid peroxidation, Fe 2+ accumulation and mitochondrial atrophy, particular in HBV-specific CD8 + T cells. Downregulation of glutathione peroxidase 4 and upregulation of CD36 were found in CD8 + T cells with high level of lipid peroxidation. Furthermore, ferroptosis is accompanied by impaired antiviral ability. Mechanistically, palmitic acid upregulates CD36...