Evidence mapPaperPMID 41872164Full record

ArticleNature communications2026

Sex-specific KDM6A-HNF4A-CREBH network controls lipoprotein cholesterol metabolism and atherosclerosis via epigenetic reprograming of hepatocytes.

Lin Chen, Zhanfang Kang, Jennifer Härdfeldt, Ziyi Li, Matteo Pedrelli, Qi Li, Ruining Lyu, Philipp Valina Allo, Taras Sych, Xiangru Zheng and 11 more

Abstract read
In one paragraph

Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

21 authors.

Lin Chen *Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Zhanfang Kang *Guangdong Engineering Technology Research Center of Urinary Continence and Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China.ORCID http://orcid.org/0000-0001-7010-8701
Jennifer HärdfeldtDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-6190-7365
Ziyi LiDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Matteo PedrelliDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0003-0771-0569
Qi LiDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Ruining LyuDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Philipp Valina AlloDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Taras SychScience for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Xiangru ZhengDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Peibin LinDepartment of Basic Medical Research, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China.
Jianwen ZengGuangdong Engineering Technology Research Center of Urinary Continence and Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China.
Zhiqiang HuangDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0001-5208-008X
Oihane Garcia-IrigoyenDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Sviatlana SukhanavaDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Paolo PariniDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Amélie BonnefondUniversity of Lille, INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, Lille University Hospital, Lille, France.ORCID http://orcid.org/0000-0001-9976-3005
Erdinc SezginScience for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-4915-388X
Bo AngelinDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-1448-2368
Eckardt TreuterDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-4147-8989
Rongrong FanDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. rongrong.fan@ki.se.ORCID http://orcid.org/0000-0002-5707-1497

Funding

Cancerfonden (Swedish Cancer Society) 232891 PjVetenskapsrådet (Swedish Research Council) 2023-02311
6 · The paper itself

Abstract

The liver is a central organ controlling lipid and cholesterol metabolism and plays a key role in regulating lipoprotein profiles and cardiovascular disease risk. Males and females show clear differences in cholesterol handling and susceptibility to atherosclerosis, but the molecular basis for these sex-specific effects remains incompletely understood. Here we show that the X-linked histone demethylase 6 A (KDM6A) is essential for maintaining healthy cholesterol metabolism in the liver. Reducing KDM6A levels in human liver cells  from females but not males disrupts gene programs involved in lipoprotein regulation linked to cardiovascular disorders. Consistently, female mice lacking KDM6A specifically in hepatocytes develops pro-atherogenic blood lipoprotein profiles and increased atherosclerosis under genetic and dietary stress, whereas males are largely unaffected. Mechanistically, KDM6A cooperates with Hepatocyte Nuclear Factor 4 Alpha (HNF4A) to promote chromatin activation and enable CREBH (encoded by CREB3L3)-dependent transcription of lipid metabolic genes. These findings identify KDM6A as a sex-linked regulator of hepatic cholesterol metabolism.

Indexed as

AtherosclerosisCholesterolCyclic AMP Response Element-Binding ProteinEpigenesis, GeneticHepatocyte Nuclear Factor 4HepatocytesHistone DemethylasesLipoproteinsAnimalsFemaleHumansLipid MetabolismLiverMaleMiceMice, Inbred C57BLCholesterolCyclic AMP Response Element-Binding ProteinHepatocyte Nuclear Factor 4Histone DemethylasesHnf4a protein, mouseKDM6A protein, humanLipoproteinsUtx protein, mouse

Identifiers

PMID41872164
PMCPMC13133126

What Socratic 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 Socratic graph.