The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells

Nat Commun. 2021 Jul 1;12(1):4068. doi: 10.1038/s41467-021-24342-y.


SARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide-a well-tolerated drug widely used in advanced prostate cancer-reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology*
  • Angiotensin-Converting Enzyme 2 / chemical synthesis
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • Benzamides / pharmacology*
  • COVID-19 / metabolism
  • COVID-19 / virology
  • COVID-19 Drug Treatment*
  • Down-Regulation / drug effects
  • Female
  • Humans
  • Lung / metabolism
  • Lung / virology
  • Male
  • Mice
  • Nitriles / pharmacology*
  • Phenylthiohydantoin / pharmacology*
  • SARS-CoV-2 / drug effects
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Virus Internalization / drug effects*


  • Androgen Antagonists
  • Benzamides
  • Nitriles
  • Phenylthiohydantoin
  • enzalutamide
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, human