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  3. Hedgehog pathway inhibitor HhAntag suppresses virus infection via the GLI-S1PR axis

Hedgehog pathway inhibitor HhAntag suppresses virus infection via the GLI-S1PR axis

  • Cell Signal. 2025 Aug:132:111807. doi: 10.1016/j.cellsig.2025.111807.
Jinyu Zhang 1,  Chunsheng Dong 2,  Zhiqiang Chen 3,  Runbin Hua 2,  Zhuozheng Li 4,  Yuzhuo Lin 5,  Yuqing Wang 6,  Tingting Feng 7,  Jianfeng Dai 8
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Infection and Immunity, Children's Hospital of Soochow University, Institute of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China; Central Laboratory, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
  • 2 Jiangsu Key Laboratory of Infection and Immunity, Children's Hospital of Soochow University, Institute of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China.
  • 3 Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
  • 4 School of Life Science and Technology, Shandong Second Medical University, Weifang 261053, China.
  • 5 The Second Clinical Medical School of Nanjing Medical University, Nanjing 211166, China.
  • 6 Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou 215000, China. Electronic address: wang_yu_qing@126.com.
  • 7 Central Laboratory, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: ttfeng@njmu.edu.cn.
  • 8 Jiangsu Key Laboratory of Infection and Immunity, Children's Hospital of Soochow University, Institute of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, China. Electronic address: daijianfeng@suda.edu.cn.
PMID: 40239727 DOI: 10.1016/j.cellsig.2025.111807
Abstract

The interplay between various signaling pathways, including tumor development, immune response, and viral Infection, suggests potential mutual regulation within biological systems. To explore this, we screened 85 inhibitors targeting the Notch, Hedgehog, and Wnt signaling pathways to identify the potential Antiviral candidates. Using two reporter viruses (VSV-GFP and DENV-Luc), we identified novel inhibitors with Antiviral properties. Notably, the Hedgehog pathway inhibitor HhAntag exhibited broad-spectrum Antiviral activity, significantly reducing the replication of viruses such as VSV, DENV, ZIKV, and SFTSV. The inhibitory effects of HhAntag were consistent with the downregulation of its target protein, GLI1; while overexpression of GLI1 promoted viral Infection. HhAntag did not interfere with viral attachment, entry, or early transcription but specifically inhibited viral protein translation. Additionally, RNA-seq analysis revealed reduced expression of sphingosine-1-phosphate (S1P) signaling pathway receptors, S1PR1 and S1PR5, following HhAntag treatment. HhAntag suppresses virus Infection via the GLI-S1PR axis. This study revealed the interplay between tumor-associated Hedgehog (Hh) pathway and viral Infection and highlights the potential of HhAntag as a broad-spectrum Antiviral drug.

Keywords

GLI1; HhAntag; Sphingosine-1-phosphate (S1P) signaling pathway receptor.

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