Evidence map›Paper›PMID 39824180›Full record

ArticleCell reports. Medicine2025

Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity.

Liming Gui, Kaiwen Chen, Jingjing Yan, Ping Chen, Wei-Qiang Gao, Bin Ma

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports. Medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.

0numbers the graph read from it
0cells of the map it votes in
19citing 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

19 citing papers in PubMed.

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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

6 authors.

Liming GuiRenji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
Kaiwen ChenRenji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
Jingjing YanRenji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
Ping ChenRenji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
Wei-Qiang GaoRenji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
Bin MaRenji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: bin.ma@outlook.com.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK family SNF1-like kinase 1 (NUAK1) is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by spliced form of X-box binding protein 1 (XBP1s) downstream of ICD-induced endoplasmic reticulum (ER) stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampens ROS and ICD, and therefore also dampens tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.

Indexed as

Immunogenic Cell DeathMevalonic AcidNeoplasmsProtein Serine-Threonine KinasesAnimalsCell Line, TumorCholesterolCRISPR-Cas SystemsEndoplasmic Reticulum StressHumansHydroxymethylglutaryl-CoA Reductase InhibitorsMiceReactive Oxygen SpeciesSimvastatinCholesterolHydroxymethylglutaryl-CoA Reductase InhibitorsMevalonic AcidProtein Serine-Threonine KinasesReactive Oxygen SpeciesSimvastatincholesterolendoplasmic reticulum stressICDimmunogenic cell deathNUAK1reactive oxygen speciesROSthe mevalonate pathwayXBP1

Identifiers

PMID39824180
PMCPMC11866496

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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.