Integrative analysis of drug-gene signatures in human pluripotent stem cells reveals prazosin as a novel SQSTM1 regulator for ALS therapeutics

  • Stem Cell Reports. 2026 Jun 25:102977. doi: 10.1016/j.stemcr.2026.102977.
Florine Roussange  1 ,  Jacqueline Gide  2 ,  Johana Tournois  3 ,  Michel Cailleret  1 ,  Anne Boland  4 ,  Christophe Battail  5 ,  Jean-François Deleuze  4 ,  Hélène Polvèche  3 ,  Didier Auboeuf  6 ,  Knut Brockmann  7 ,  Edor Kabashi  8 ,  Anca Marian  8 ,  Lina El Kassar  3 ,  Sophie Blondel  2 ,  François Salachas  9 ,  Gaëlle Bruneteau  10 ,  Marc Peschanski  2 ,  Cécile Martinat  11 ,  Sandrine Baghdoyan  1
Affiliations
  • 1. Université Paris Saclay, Université d'Evry, Inserm, IStem, UMR861, 91100 Corbeil-Essonnes, France.
  • 2. IStem, CECS, 91100 Corbeil-Essonnes, France.
  • 3. IStem, CECS, the research and innovation team, 91100 Corbeil-Essonnes, France.
  • 4. Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057 Evry, France.
  • 5. Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057 Evry, France; Université Grenoble Alpes, Inserm, CEA, UA13, BGE, 38000 Grenoble, France.
  • 6. Ecole Normale Supérieure de Lyon, Inserm, U1293, CNRS, UMR 5239, Université Claude Bernard Lyon 1, Laboratory of Biology and Modelling of the Cell, 46 allée d'Italie 69364 Lyon, France.
  • 7. Department of Pediatrics and Adolescent Medicine, University Medical Center, Göttingen, Germany.
  • 8. Laboratory of Translational Research for Neurological Disorders, Imagine Institute, Université de Paris, INSERM, UMR 1163, 75015 Paris, France.
  • 9. Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, APHP, Inserm, CNRS, Département de Neurologie, Centre SLA de Paris, Hôpital Pitié-Salpêtrière, 75013 Paris, France.
  • 10. Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, APHP, Inserm, CNRS, Département de Neurologie, Centre SLA de Paris, Hôpital Pitié-Salpêtrière, 75013 Paris, France; Alliance on Clinical Trials for ALS-MND (ACT4ALS-MND), Neuroscience Clinical Investigation Center, Paris Brain Institute, 75013 Paris, France.
  • 11. Université Paris Saclay, Université d'Evry, Inserm, IStem, UMR861, 91100 Corbeil-Essonnes, France; IStem, CECS, 91100 Corbeil-Essonnes, France. Electronic address: [email protected].
PMID: 42349423 DOI: 10.1016/j.stemcr.2026.102977
Abstract

The classical paradigm of drug screening often faces significant limitations due to the challenges associated with identifying molecular or cellular read-outs that are relevant to specific genetic diseases. To remedy this, an alternative approach of reverse phenotypic mapping was tested: Compounds were evaluated for their effects on gene expression and alternative splicing in a healthy cell model, and the resulting data were matched to molecular signatures of diseases. A subset of 50 drugs was tested on mesenchymal stem cells derived from a human pluripotent stem cell line. Over half of the compounds altered gene expression, many affecting pathways linked to monogenic diseases. One hit, increased SQSTM1 expression induced by prazosin, was further validated in FTD/ALS type 3 models caused by SQSTM1 haploinsufficiency, including patient-derived fibroblasts, SQSTM1-depleted hiPSC-derived motor neurons, and a zebrafish model. Extending this paradigm could involve testing diverse cell types and larger drug libraries.

Keywords
SQSTM1; amyotrophic lateral sclerosis; autophagy; drug repositioning; gene expression mapping; motor neurons; personalized therapies; pluripotent stem cells; repurposing.
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