HBcAg-Induced IL-17F drives liver fibrosis in occult HBV infection

While occult hepatitis B virus infection is a known risk factor for progressive liver diseases, the mechanistic basis for this association is poorly understood. To investigate this, we conducted a comparative study involving 40 OBI blood donors and 100 healthy blood donors to assess clinical parameters of liver fibrosis, including serum biomarkers, the FIB-4 index, and liver stiffness measurement. Transcriptome sequencing of peripheral blood mononuclear cells from these donors identified IL-17F as significantly upregulated in the OBI group. Mechanistically, we found that IL-17F was chiefly secreted by CD4⁺ T cells upon HBcAg stimulation and functionally promoted the expression of key fibrosis-related cytokines and markers. Collectively, our study unveils a novel pathway wherein HBcAg induces CD4⁺ T cells to secrete IL-17F, which in turn accelerates liver fibrogenesis, providing a mechanistic basis for OBI-associated liver disease.IMPORTANCEThis study reveals, for the first time, a novel mechanism by which OBI drives liver fibrosis, demonstrating that HBcAg stimulates CD4⁺ T cells to secrete IL-17F, which in turn activates macrophages and hepatic stellate cells, thereby promoting liver inflammation and fibrosis. This discovery not only elucidates a key molecular pathway underlying OBI-related liver disease progression, but also provides an important theoretical foundation for developing IL-17F-targeted diagnostic approaches and anti-fibrotic therapies.