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<p>Influenza A viruses subvert lysosomal function to evade host degradation mechanisms. Using Connectivity Map (CMap) screening and transcriptomic analysis, we identified fangchinoline (Fan)—a bisbenzylisoquinoline alkaloid—as a potent enhancer of lysosomal gene expression. Owing to its alkaline properties, Fan accumulates within lysosomes, elevates luminal pH, and induces TFEB nuclear translocation, thereby restoring lysosomal biogenesis and initiating a TFEB-driven antiviral response. Concurrently, Fan disrupts autophagosome–lysosome fusion and impairs autophagic flux, further enhancing its antiviral activity. Time-resolved functional assays demonstrate that Fan primarily inhibits H1N1 infection at the entry stage by obstructing endolysosomal trafficking. Together, these results identify Fan as a novel TFEB-mediated lysosomal modulator that antagonizes influenza infection by counteracting viral lysosomal evasion strategies and highlighting the therapeutic potential of lysosome-targeted compounds in influenza treatment.</p>

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Fangchinoline restores TFEB-driven lysosomal biogenesis and blocks H1N1 infection

  • 期刊论文

  • 发表日期：

    2026年4月2日

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  • Cui-qin Cheng,
  • Fang Xie,
  • Zhe Liu,
  • Jun-liang Li,
  • Yuan-yuan Qiao,
  • Ling-dong Kong,
  • Qi-qi Li,
  • Ke-xin Ma,
  • Fei Liu,
  • Liang-dong Song,
  • Han Wang,
  • Yao Wang,
  • Xin Jia

摘要

Influenza A viruses subvert lysosomal function to evade host degradation mechanisms. Using Connectivity Map (CMap) screening and transcriptomic analysis, we identified fangchinoline (Fan)—a bisbenzylisoquinoline alkaloid—as a potent enhancer of lysosomal gene expression. Owing to its alkaline properties, Fan accumulates within lysosomes, elevates luminal pH, and induces TFEB nuclear translocation, thereby restoring lysosomal biogenesis and initiating a TFEB-driven antiviral response. Concurrently, Fan disrupts autophagosome–lysosome fusion and impairs autophagic flux, further enhancing its antiviral activity. Time-resolved functional assays demonstrate that Fan primarily inhibits H1N1 infection at the entry stage by obstructing endolysosomal trafficking. Together, these results identify Fan as a novel TFEB-mediated lysosomal modulator that antagonizes influenza infection by counteracting viral lysosomal evasion strategies and highlighting the therapeutic potential of lysosome-targeted compounds in influenza treatment.