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Fangchinoline restores TFEB-driven lysosomal biogenesis and blocks H1N1 infection

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

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.

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Fig. 1: Fan mitigates the lysosomal damage induced by H1N1.
Fig. 2: Fan inhibits H1N1 in vitro.
Fig. 3: Fan inhibits H1N1 replication and reduces inflammation caused by virus in vivo.
Fig. 4: Fan interferes with the H1N1 virus life cycle at the entry stage.
Fig. 5: Fan accumulates within lysosomes and inhibits acidification to antagonize H1N1.
Fig. 6: Fan hijacks the autophagy-lysosome pathway to degrade viral components.
Fig. 7: The regulation of autophagy-lysosome system and antiviral effect of Fan depends on TFEB.

Data availability

Data will be made available on request.

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Acknowledgements

We would like to thank Prof. Feng Shao (National Institute of Biological Sciences, Beijing, China) for kindly providing iBMDM cells, Prof. Xin-jian Li (Institute of Biophysics, Chinese Academy of Sciences, Beijing, China) for kindly providing NC and Tfeb−/− iBMDM cells, as well as Prof. Kun-peng Liu (Guangxi University, Nanning, Guangxi, China) for providing the LC3B-EGFP-mCherry and LC3-EGFP plasmids. We would also like to express our gratitude to everyone who contributed to or supported this research project. Graphical Abstract was created by Figdraw.

Funding

This work is funded by the National Science and Technology Major Projects (2024ZD0523400), National Natural Science Foundation of China (82474153), the Beijing Natural Science Foundation (7242239), the Beijing Nova Program (Grant NO. 20230484342 and 20240484706) and the Young Elite Scientists Sponsorship Program by China Association of Chinese Medicine (Grant NO. 2023-QNRC2-A02).

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Author notes

  1. These authors contributed equally: Cui-qin Cheng, Fang Xie, Zhe Liu, Jun-liang Li.

Authors and Affiliations

  1. Beijing University of Chinese Medicine, Beijing, 100029, China

    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

  2. Shandong University of Engineering and Vocational Technology, Ji-nan, 250200, China

    Fang Xie

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Contributions

XJ, YW and HW conceptualized the paper. CQC, FX, ZL, JLL drafted the paper. CQC, FX, ZL, JLL, YYQ, LDK, QQL, KXM, FL, LDS, HW performed experiments and/or data collection. YW obtained funding. YW, XJ revised and edited the manuscript. All authors have read and approved this manuscript. CQC: Writing-review & editing, Writing-original draft, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. FX: Writing-original draft, Methodology, Investigation, Formal analysis, Conceptualization. ZL: Writing-review & editing, Methodology, Investigation, Formal analysis. JLL: Writing-review & editing, Methodology, Investigation YYQ: Methodology, Investigation, Formal analysis. LDK: Methodology, Investigation. QQL: Methodology, Investigation. KXM: Methodology, Investigation. FL: Methodology, Investigation. LDS: Methodology, Investigation. HW: Methodology, Investigation, Formal analysis. YW: Writing-review & editing, Validation, Resources, Project administration, Funding acquisition, Conceptualization. XJ: Writing-review & editing, Validation, Project administration, Formal analysis, Conceptualization.

Corresponding authors

Correspondence to Han Wang, Yao Wang or Xin Jia.

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The authors acknowledge the patent (ZL 2022 1 0976106.X), relating to this work, owned by Beijing University of Chinese Medicine. No financial benefits have been received to date.

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Cheng, Cq., Xie, F., Liu, Z. et al. Fangchinoline restores TFEB-driven lysosomal biogenesis and blocks H1N1 infection. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01776-y

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