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Tetrandrine-driven autophagy suppresses SARS-CoV-2 replication by modulating cholesterol and IGF signaling pathways
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  • Published: 06 January 2026

Tetrandrine-driven autophagy suppresses SARS-CoV-2 replication by modulating cholesterol and IGF signaling pathways

  • Lais de O. Marchioro1,2 na1,
  • Sofia De Stefanis3 na1,
  • Beatriz G. Araújo1,
  • Davide Mariotti4,
  • Ingrid K. M. Watanabe5,
  • Michael Stumpe  ORCID: orcid.org/0000-0002-9443-93266,
  • Giulia Matusali4,
  • Fabrizio Maggi2,4,
  • Soraya S. Smaili  ORCID: orcid.org/0000-0001-5844-13681,
  • Jörn Dengjel  ORCID: orcid.org/0000-0002-9453-46146,
  • Gustavo J. S. Pereira1,7 na2 &
  • …
  • Manuela Antonioli  ORCID: orcid.org/0000-0002-7568-47132,8 na2 

Cell Death Discovery , Article number:  (2026) Cite this article

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Subjects

  • Antiviral agents
  • Autophagy
  • Target identification

Abstract

SARS-CoV-2 exploits multiple host cellular processes, including autophagy, a critical intracellular degradation pathway, to facilitate viral replication and evade immune detection. Tetrandrine, a natural bis-benzylisoquinoline alkaloid derived from Stephania tetrandra, has been reported to modulate autophagy and exhibits potential antiviral properties. In this study, we investigated the effects of Tetrandrine on SARS-CoV-2 infection in human lung epithelial cells (Calu-3), with a particular focus on autophagy-related mechanisms. Our results demonstrate that Tetrandrine modulates autophagic activity in a dose-dependent manner and significantly reduces SARS-CoV-2 replication, particularly when administered prior to infection. Notably, its antiviral effect is retained in autophagy-deficient cells, indicating the involvement of autophagy-independent mechanisms. Proteomic analysis of Calu-3 cells infected with the Omicron BA.5 variant revealed that Tetrandrine regulates several host pathways implicated in viral replication, including autophagy, cholesterol metabolism, and insulin-like growth factor signaling. These findings suggest that Tetrandrine exerts multifaceted antiviral effects by targeting both autophagy-dependent and -independent cellular pathways. Collectively, our data supports the potential of Tetrandrine as a therapeutic candidate against COVID-19 and warns further evaluation in preclinical and clinical models. Data are available via ProteomeXchange with identifier PXD064448.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Dr. Daniele Lapa for the BSL3 laboratory formation of L.O.M. at IRCCS INMI L. Spallanzani. Mohammadreza Bayat and Nesilda Qaja for sustaining M.A. in leading the IRCCS INMI L. Spallanzani laboratory activity and Confocal Images analysis, respectively. Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, at Unicamp, specially to Dr. Jose Luiz Proença-Modena and the group of researchers, supporting the discussion of results and BSL3 laboratory formation of L.O.M. in Brazil.

Funding

This study received support from Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP: 2019/14722-4; 2022/15748-0 (G.J.S.P.); 2019/02821-8 (S.S.S.). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES and CAPES/PrInt) - Finance Code 001 for scholarship to L.O.M. The study has also been funded by the University and the Canton of Fribourg as part of the SKINTEGRITY.CH research network to J.D., by the Biology Department of Tor Vergata University of Rome (project acronym, AutoCuRC) to M.A., supported by the Italian Ministry of Health with Ricerca Corrente Linea 1 to IRCCS INMI L. Spallanzani (F.M.), and Ricerca Finalizzata (GR-2019-12369231) to M.A.

Author information

Author notes

  1. These authors contributed equally: Lais de O. Marchioro, Sofia De Stefanis.

  2. These authors jointly supervised this work: Gustavo J. S. Pereira, Manuela Antonioli.

Authors and Affiliations

  1. Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil

    Lais de O. Marchioro, Beatriz G. Araújo, Soraya S. Smaili & Gustavo J. S. Pereira

  2. Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases “Lazzaro Spallanzani”- IRCCS 00149, Rome, Italy

    Lais de O. Marchioro, Fabrizio Maggi & Manuela Antonioli

  3. PhD Program in Cellular and Molecular Biology, Department of Biology, University of Rome “Tor Vergata”, 00133, Rome, Italy

    Sofia De Stefanis

  4. Laboratory of Virology and Laboratories of Biosafety, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149, Rome, Italy

    Davide Mariotti, Giulia Matusali & Fabrizio Maggi

  5. Nephrology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil

    Ingrid K. M. Watanabe

  6. Department of Biology, University of Fribourg, 1700, Fribourg, Switzerland

    Michael Stumpe & Jörn Dengjel

  7. Department of Cell and Developmental Biology, University College London, London, UK

    Gustavo J. S. Pereira

  8. Department of Biology, University of Rome “Tor Vergata”, 00133, Rome, Italy

    Manuela Antonioli

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Contributions

L.O.M., S.D.S. G.M., S.S.S., G.M.F., G.J.S.P., M.A. conceptualization; L.O.M., S.D.S., B.G.A, I.K.M.W., D.M., M.S., G.M., G.J.S.P, M.A. methodology; L.O.M., S.D.S., D.M., G.M., M.A. data curation; G.J.S.P., S.S.S., L.O.M., F.M., J.D., M.A. funding acquisition; G.M., G.J.S.P., M.A. supervision and validation; L.O.M., I.K.M.W., S.S.S., F.M., J.D., G.J.S.P., M.A. writing – review & editing; L.O.M.; G.J.S.P.; M.A. writing – original draft. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Gustavo J. S. Pereira or Manuela Antonioli.

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Marchioro, L.d.O., De Stefanis, S., Araújo, B.G. et al. Tetrandrine-driven autophagy suppresses SARS-CoV-2 replication by modulating cholesterol and IGF signaling pathways. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-025-02926-7

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  • Received: 23 June 2025

  • Revised: 04 December 2025

  • Accepted: 12 December 2025

  • Published: 06 January 2026

  • DOI: https://doi.org/10.1038/s41420-025-02926-7

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