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ResearchIn-Press PreviewAgingPulmonology Open Access | 10.1172/JCI173371
1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
Find articles by Lee, J. in: JCI | PubMed | Google Scholar
1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
Find articles by Reyes, N. in: JCI | PubMed | Google Scholar
1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
Find articles by Ravishankar, S. in: JCI | PubMed | Google Scholar
1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
Find articles by Zhou, M. in: JCI | PubMed | Google Scholar
1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
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1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Francisco, United States of America
2Small Molecule Discovery Center, University of California San Francisco, San Francisco, United States of America
3Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and, University of California San Francisco, San Fransisco, United States of America
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Published March 7, 2024 - More info
The appearance of senescent cells in age-related diseases has spurred the search for compounds that can target senescent cells in tissues (“senolytics”). However, a major caveat with current senolytic screens is the use of cell lines as targets where senescence is induced in vitro, which does not necessarily reflect the identity and function of pathogenic senescent cells in vivo. Here, we developed a new pipeline leveraging a fluorescent murine reporter that allows for isolation and quantification of p16Ink4a+ cells in diseased tissues. By high-throughput screening in vitro, precision cut lung slice (PCLS) screening ex vivo, and phenotypic screening in vivo, we identified a HSP90 inhibitor (XL888) as a potent senolytic in tissue fibrosis. XL888 treatment eliminated pathogenic p16Ink4a+ fibroblasts in a murine model of lung fibrosis and reduced fibrotic burden. Finally, XL888 preferentially targeted p16INK4a-high human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), and reduced p16INK4a+ fibroblasts from IPF PCLS ex vivo. This study provides proof of concept for a platform where p16INK4a+ cells are directly isolated from diseased tissues to identify compounds with in vivo and ex vivo efficacy in mouse and human respectively and provides a senolytic screening platform for other age-related diseases.