Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration

Proc Natl Acad Sci U S A. 2021 Oct 12;118(41):e2102975118. doi: 10.1073/pnas.2102975118.


The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA-induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD.

Keywords: fluoxetine; health insurance databases; macular degeneration; molecular modeling; retina.

Publication types

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

MeSH terms

  • Alu Elements / genetics
  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology*
  • Blindness / pathology
  • Blindness / prevention & control
  • Cell Line
  • Cytokines / metabolism
  • Depression / drug therapy
  • Disease Models, Animal
  • Drug Repositioning / methods*
  • Fluoxetine / pharmacology*
  • Inflammasomes / metabolism
  • Macrophages / immunology
  • Macular Degeneration / drug therapy*
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • RNA / genetics
  • Retina / pathology
  • Retinal Pigment Epithelium / cytology
  • Retinal Pigment Epithelium / drug effects*
  • Retinal Pigment Epithelium / pathology


  • Antidepressive Agents, Second-Generation
  • Cytokines
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Fluoxetine
  • RNA