A phenopushing platform to identify compounds that alleviate acute hypoxic stress by fast-tracking cellular adaptation

Li Li; Heinz Hammerlindl; Susan Q Shen; Feng Bao; Sabrina Hammerlindl; Steven J Altschuler; Lani F Wu

doi:10.1038/s41467-025-57754-1

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A phenopushing platform to identify compounds that alleviate acute hypoxic stress by fast-tracking cellular adaptation

Journal article

Open access

Peer reviewed

A phenopushing platform to identify compounds that alleviate acute hypoxic stress by fast-tracking cellular adaptation

Li Li, Heinz Hammerlindl, Susan Q Shen, Feng Bao, Sabrina Hammerlindl, Steven J Altschuler and Lani F Wu

Nature communications, Vol.16(1), 2684

03/18/2025

DOI: 10.1038/s41467-025-57754-1

PMCID: PMC11920246

PMID: 40102413

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Abstract

Severe acute hypoxic stress is a major contributor to the pathology of human diseases, including ischemic disorders. Current treatments focus on managing consequences of hypoxia, with few addressing cellular adaptation to low-oxygen environments. Here, we investigate whether accelerating hypoxia adaptation could provide a strategy to alleviate acute hypoxic stress. We develop a high-content phenotypic screening platform to identify compounds that fast-track adaptation to hypoxic stress. Our platform captures a high-dimensional phenotypic hypoxia response trajectory consisting of normoxic, acutely stressed, and chronically adapted cell states. Leveraging this trajectory, we identify compounds that phenotypically shift cells from the acutely stressed state towards the adapted state, revealing mTOR/PI3K or BET inhibition as strategies to induce this phenotypic shift. Importantly, our compound hits promote the survival of liver cells exposed to ischemia-like stress, and rescue cardiomyocytes from hypoxic stress. Our "phenopushing" platform offers a general, target-agnostic approach to identify compounds and targets that accelerate cellular adaptation, applicable across various stress conditions.

Phenotype

Adaptation, Physiological - drug effects

Animals

Cell Hypoxia - drug effects

Cell Survival - drug effects

High-Throughput Screening Assays - methods

Humans

Hypoxia - drug therapy

Hypoxia - metabolism

Mice

Myocytes, Cardiac - drug effects

Myocytes, Cardiac - metabolism

Phosphatidylinositol 3-Kinases - metabolism

Signal Transduction - drug effects

Stress, Physiological - drug effects

TOR Serine-Threonine Kinases - metabolism

Details

Title: Subtitle: A phenopushing platform to identify compounds that alleviate acute hypoxic stress by fast-tracking cellular adaptation
Creators: Li Li - University of California, San Francisco
Heinz Hammerlindl - University of California, San Francisco
Susan Q Shen - University of California, San Francisco
Feng Bao - University of California, San Francisco
Sabrina Hammerlindl - University of California, San Francisco
Steven J Altschuler - University of California, San Francisco
Lani F Wu - University of California, San Francisco
Resource Type: Journal article
Publication Details: Nature communications, Vol.16(1), 2684
DOI: 10.1038/s41467-025-57754-1
PMID: 40102413
PMCID: PMC11920246
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: NATURE PORTFOLIO
Grant note: R25MH0602 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) LT000908/2020-C / Human Frontier Science Program (HFSP) HR0011-19-2-0018 / United States Department of Defense | Defense Advanced Research Projects Agency (DARPA) R38AG070171 / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
Language: English
Date published: 03/18/2025
Academic Unit: Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984801668902771

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