Evidence map›Paper›PMID 41370380›Full record

ArticleScience advances2025

HERVH-derived eRNA activates a super-enhancer-driven ALDH1A3/SAT1 axis to promote ferroptosis escape and pancreatic cancer development.

Lili Yuan, Jiahui Yu, Xiaoli Xu, Yiwen Huang, Dianhui Wei, Zhenbo Hou, Huizhen Nie, Tiantian Jing, Yizhen Liu, Boshi Wang

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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 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

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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

1 citing paper in PubMed.

  1. Review
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

10 authors.

Lili YuanState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.ORCID 0009-0008-4589-0795
Jiahui YuState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.ORCID 0009-0006-4963-3564
Xiaoli XuState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.ORCID 0009-0000-1099-7834
Yiwen HuangState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
Dianhui WeiState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.ORCID 0000-0002-1287-064X
Zhenbo HouDepartment of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Huizhen NieState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
Tiantian JingState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.ORCID 0009-0007-6149-8200
Yizhen LiuDepartment of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.ORCID 0000-0002-1320-7364
Boshi WangState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.ORCID 0000-0001-6923-2588

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Endogenous retroviruses (ERVs), widely distributed in the human genome, are usually epigenetically silenced but can be reactivated in cancer. Activated ERVs may act as regulatory elements or produce noncoding RNAs that modulate gene expression and affect tumor biology. Their role in pancreatic ductal adenocarcinoma (PDAC), particularly in ferroptosis regulation, remains unclear. Here, we identify human endogenous retrovirus-H (HERVH) derived enhancer RNAs (eRNAs) aberrantly overexpressed in PDAC by integrating gene expression and histone modification data. Silencing HERVH markedly suppresses PDAC proliferation and tumor growth. Mechanistically, HERVH transcription is driven by the super-enhancer-associated transcription factor Krüppel-like factor 5 (KLF5), and HERVH eRNAs cooperate with KLF5 to transactivate a distal super-enhancer upstream of aldehyde dehydrogenase family 1 member 3 (ALDH1A3), increasing its expression. ALDH1A3 inhibits the reactive oxygen species/specificity protein 1/spermidine/spermine N1-acetyltransferase 1 (ROS/Sp1/SAT1) cascade, reducing lipid peroxidation and ferroptosis. Disrupting this axis induces ferroptotic death and impairs PDAC development. Our study reveals a previously unrecognized mechanism in which HERVH-derived eRNAs regulate ferroptosis via super-enhancer-mediated transcriptional reprogramming and highlights the KLF5/HERVH/ALDH1A3 pathway as a potential therapeutic target in PDAC.

Indexed as

Aldehyde OxidoreductasesCarcinoma, Pancreatic DuctalEnhancer Elements, GeneticFerroptosisPancreatic NeoplasmsAnimalsCell Line, TumorCell ProliferationGene Expression Regulation, NeoplasticHumansKruppel-Like Transcription FactorsMiceAldehyde OxidoreductasesKLF5 protein, humanKruppel-Like Transcription Factors

Identifiers

PMID41370380
PMCPMC12693981

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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.