2. Academic Validation
  3. FTY720 alleviates HBV-mediated inflammatory liver injury through a dual role of inhibiting lymphocyte trafficking and viral replication

FTY720 alleviates HBV-mediated inflammatory liver injury through a dual role of inhibiting lymphocyte trafficking and viral replication

  • Int Immunopharmacol. 2025 Apr 24:153:114495. doi: 10.1016/j.intimp.2025.114495.
Juan Liu 1,  Yin-Xia Zhao 2,  Ya-Hui Song 1,  Lu Zhang 3,  Xiu Han 1,  Le Liu 1,  Min Li 4,  Lin Wang 1,  Yu-Min Wu 5,  Qing-Zhen Han 6
Affiliations

Affiliations

  • 1 Center of Clinical Laboratory and Translational Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, PR China.
  • 2 Central Laboratory, Shanghai Xuhui Central Hospital/Zhongshan-Xuhui Hospital, Fudan University, Shanghai, PR China.
  • 3 Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, PR China.
  • 4 Institute of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, PR China.
  • 5 Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, PR China.
  • 6 Center of Clinical Laboratory and Translational Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, PR China. Electronic address: gyhqz2021@163.com.
PMID: 40121743 DOI: 10.1016/j.intimp.2025.114495
Abstract

Background: The host immune response plays a critical role in clearing hepatitis B virus Infection. However, in chronic hepatitis B, this response fails to eliminate the virus, leading to recurrent inflammation, liver tissue damage, and a gradual progression from hepatitis to fibrosis, and eventually, hepatocellular carcinoma. Reducing liver injury while enhancing Antiviral efficacy remains a key objective in hepatitis B virus treatment development. Our previous research revealed a close association between hepatitis B virus Infection and the sphingosine 1-phosphate signaling pathway. Consequently, this study aims to explore the dual role of FTY720, an immune modulator that targets sphingosine- 1-phosphate receptor, in hepatitis B virus-related liver injury.

Methods: In this study, The peripheral blood leukocyte count and the expression of sphingosine 1-phosphate receptor on lymphocytes were compared between chronic hepatitis B patients and healthy controls. In vitro experiments were conducted to evaluate the direct Antiviral effects of FTY720 on two hepatitis B virus models: HepG2.2.15 and Huh7 cells transfected with pUC19-HBV1.3. Additionally, the study investigated the influence of FTY720 on the chemotaxis of peripheral blood mononuclear cells induced by the supernatant of hepatitis B virus-infected HepG2-NTCP cells. An in vivo model using hepatitis B virus hyperbaric hydrodynamic injection in mice was also employed to assess the impact of FTY720 on both HBV replication and hepatic lymphocyte infiltration.

Results: Peripheral blood lymphocyte counts were reduced, while sphingosine 1-phosphate receptor expression was elevated in chronic hepatitis B patients compared to healthy controls. Simultaneously, Antiviral therapy solely utilizing nucleotide analogues could not fully restore the peripheral blood lymphocyte count in patients with chronic hepatitis B. In vitro, FTY720 effectively inhibited hepatitis B virus replication in two models: HepG2.2.15 cells containing hepatitis B virus virions and pUC19-HBV1.3-transfected Huh7 cells. Furthermore, supernatants from hepatitis B virus-infected HepG2-NTCP cells induced increased lymphocyte chemotaxis, which was suppressed by FTY720. In a hepatitis B virus mouse model, FTY720 significantly reduced viral DNA and protein levels, while also decreasing inflammatory hepatocyte necrosis, liver lymphocyte infiltration, and sphingosine 1-phosphate receptor expression on circulating lymphocytes.

Conclusions: These findings suggest that FTY720 can inhibit both hepatitis B virus replication and hepatitis B virus-related liver damage by modulating lymphocyte migration. Further investigation into the specific mechanisms underlying the interaction between FTY720 and hepatitis B virus is warranted.

Keywords

FTY720; HBV; Lymphocyte trafficking; S1PRs; Sphingosine 1-phosphate.

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