Evidence map›Paper›PMID 41160678›Full record

ArticleScience advances2025

Pharmacological targeting of RIG-I can selectively activate the integrated stress response.

Caroline A Cuoco, Wen Ren, Kelsey R Baron, Sakina Gologo, Valerie Perea, Prakhyat Mathur, Prerona Bora, Amina Ta, Alan Chu, Rama Aldakhlallah and 14 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors.

Caroline A CuocoDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0009-0002-0690-6391
Wen RenDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0009-0001-4241-4151
Kelsey R BaronDepartment of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA.
Sakina GologoDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0009-0000-3479-1160
Valerie PereaDepartment of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA.
Prakhyat MathurDepartment of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0000-0002-3129-4465
Prerona BoraDepartment of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0000-0002-3489-6146
Amina TaDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
Alan ChuThe California Institute for Biomedical Research, La Jolla, CA, USA.ORCID 0000-0002-6669-9649
Rama AldakhlallahDepartment of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0009-0008-5833-0244
Derek RhoadesDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0000-0002-9536-424X
Christian M ColeDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Ee Phie TanDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0000-0003-1352-0366
William C HouDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0009-0009-8635-438X
Leonard YoonDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0000-0002-8663-5757
Xiaoyan GuoInstitute for Neurodegenerative diseases, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0002-9388-484X
Jessica D RosardaDepartment of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0000-0002-2742-7413
Phil S BaranDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0000-0001-9193-9053
Martin KampmannInstitute for Neurodegenerative diseases, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0002-3819-7019
Lakeisha TilleryThe California Institute for Biomedical Research, La Jolla, CA, USA.ORCID 0009-0000-7862-5375
Kristen A JohnsonThe California Institute for Biomedical Research, La Jolla, CA, USA.ORCID 0000-0003-0788-7217
Evan T PowersDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0000-0001-8185-8487
R Luke WisemanDepartment of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0000-0001-9287-6840
Jeffery W KellyDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0000-0001-8943-3395

Funding

Discovering small molecules activators of stress responsive signalingR01AG046495 · NIA · SCRIPPS RESEARCH INSTITUTE, THE · PI JEFFERY W KELLY, Rockland Luke Wiseman · 2013 to 2026
$6.0M
IMPACTING MITOCHONDRIAL FUNCTION THROUGH ALTERED PROTEASE ACTIVITYR01NS095892 · NINDS · SCRIPPS RESEARCH INSTITUTE, THE · PI WISEMAN, ROCKLAND LUKE · 2016 to 2025
$5.3M
Discovering Small Molecule Activators of Stress-Responsive SignalingRF1AG046495 · NIA · SCRIPPS RESEARCH INSTITUTE, THE · PI KELLY, JEFFERY W, WISEMAN, ROCKLAND LUKE · 2023 to 2025
$2.8M
Pharmacologic Lysosomal Flux Activators to Ameliorate Alzheimer's Disease and Related DementiasRF1AG073418 · NIA · SCRIPPS RESEARCH INSTITUTE, THE · PI KELLY, JEFFERY W · 2021 to 2021
$2.6M
Pharmacologic Lysosomal Flux Activators to Ameliorate Alzheimer's Disease and Related DementiasR01AG073418 · NIA · SCRIPPS RESEARCH INSTITUTE, THE · PI JEFFERY W KELLY · 2024 to 2026
$2.5M
Defining Endoplasmic Reticulum Stress-Development Mitochondria RemodelingRF1NS125674 · NINDS · SCRIPPS RESEARCH INSTITUTE, THE · PI WISEMAN, ROCKLAND LUKE · 2022 to 2022
$2.4M
Defining Endoplasmic Reticulum Stress-Development Mitochondria RemodelingR01NS125674 · NINDS · SCRIPPS RESEARCH INSTITUTE, THE · PI Rockland Luke Wiseman · 2025 to 2026
$1.4M
NIA NIH HHS R01 AG046495NIA NIH HHS R01 AG073418NIA NIH HHS RF1 AG046495NIA NIH HHS RF1 AG073418NINDS NIH HHS R01 NS095892NINDS NIH HHS R01 NS125674NINDS NIH HHS RF1 NS125674
6 · The paper itself

Abstract

The integrated stress response (ISR) is a eukaryotic stress-responsive signaling pathway that attenuates global protein synthesis while allowing selective translation of specific mRNAs, which together can reestablish homeostasis following acute stress. Diverse pathologic insults activate one or more of the four ISR kinases, which selectively phosphorylate eIF2α to mediate ISR functions. Recent results suggest that enhancing ISR kinase activity could ameliorate pathologies linked to numerous diseases, including many neurodegenerative disorders. However, few pharmacological strategies exist to selectively activate ISR kinases and downstream adaptive signaling. Here, we report that compound A8 can preferentially activate the ISR through the binding of the cytosolic pattern recognition receptor RIG-I, which subsequently activates the heme-regulated inhibitor (HRI) ISR kinase independent of an interferon response. The establishment of A8 and its active metabolite CC81 provides opportunities to probe the biological and therapeutic relationship between innate immune signaling and ISR activation in health and disease.

Indexed as

DEAD Box Protein 58Stress, PhysiologicalAnimalsHEK293 CellsHumansImmunity, InnateMiceReceptors, ImmunologicSignal TransductionDEAD Box Protein 58Receptors, ImmunologicRIGI protein, human

Identifiers

PMID41160678
PMCPMC12571054

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.