Evidence map›Paper›PMID 41417568›Full record

ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026

DNMT2-m5C-ACLY Axis Promotes Lenvatinib Resistance in Hepatocellular Carcinoma Through Histone Acetylation-Mediated Notch Pathway.

Shiguang Yang, Jie Li, Shengwei Mao, Xuhui Zhao, Douwaner Liu, Jiafeng Chen, Jialu Fu, Yichao Bu, Xiaoling Wu, Shaoqing Liu and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing 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

5 citing papers in PubMed.

  1. NSUN2-Mediated mAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Article
  2. mBiology direct · 2026
    Review
  3. Review
  4. Review
  5. 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

15 authors.

Shiguang YangDepartment of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Jie LiNational Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Shengwei MaoDepartment of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Xuhui ZhaoDepartment of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Douwaner LiuDepartment of Radiation Oncology, Huadong Hospital, Fudan University, Shanghai, China.
Jiafeng ChenDepartment of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Jialu FuDepartment of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Yichao BuDepartment of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Xiaoling WuDepartment of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Shaoqing LiuDepartment of Breast Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
Qifeng YuDepartment of Hepatobiliary Surgery, Zhoushan Hospital, Zhoushan, China.
Qiongzhu DongDepartment of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Minhang Hospital, Fudan University, Shanghai, China.
Zheng TangDepartment of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Yuan FangDepartment of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Yinghong ShiDepartment of Hepatobiliary Surgery and Liver Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.ORCID https://orcid.org/0000-0002-1833-8988

Funding

Clinical research projects of Zhongshan Hospital Affiliated to Fudan University H2021-021National Natural Science Foundation of China 82273386National Natural Science Foundation of China 82273387National Natural Science Foundation of China 82403555National Natural Science Foundation of China 82573205Youth Fund of Zhongshan Hospital Affiliated to Fudan University 2023ZSQN16Youth Fund of Zhongshan Hospital Affiliated to Fudan University 2023ZSQN47
6 · The paper itself

Abstract

Lenvatinib serves as a first-line therapy for advanced hepatocellular carcinoma (HCC), but its clinical efficacy is severely limited by acquired drug resistance. Consequently, the identification of therapeutic targets to reverse lenvatinib resistance may offer novel strategies to achieve enhanced and durable treatment responses. In this study, a global elevation in the levels of m5C modification is observed in lenvatinib-resistant cells compared with their parental counterparts. DNA methyltransferase 2(DNMT2), functioning as an RNA methyltransferase, is markedly upregulated in lenvatinib-resistant specimens and correlated with poor patient survival outcomes. Both in vitro and in vivo experiments indicated that DNMT2 downregulation effectively overcame lenvatinib resistance by reducing HCC cell proliferation and promoting apoptosis, thereby restoring drug sensitivity. Mechanistically, DNMT2 functioned together with Y-box binding protein 1 (YBX1) to stabilize downstream adenosine triphosphate citrate lyase (ACLY) mRNA through m5C modification. This process activated the Notch signaling pathway by increasing intracellular acetyl-CoA levels and promoting histone acetylation, driving the progression of lenvatinib resistance. Critically, pharmacological inhibition of ACLY combined with lenvatinib treatment enhanced the therapeutic efficacy against HCC and could reduce the tumor burden in multiple preclinical models. Collectively, the findings indicate the importance of the DNMT2-ACLY-NOTCH signaling axis in lenvatinib resistance and propose novel combinatorial therapies to improve HCC treatment outcomes.

Indexed as

Carcinoma, HepatocellularDrug Resistance, NeoplasmHistonesLiver NeoplasmsPhenylurea CompoundsQuinolinesReceptors, NotchAcetylationAnimalsAntineoplastic AgentsCell Line, TumorCell ProliferationHumansMiceMice, NudeSignal TransductionAntineoplastic AgentsHistoneslenvatinibPhenylurea CompoundsQuinolinesReceptors, Notchhepatocellular carcinomahistone acetylationlenvatinib resistancem5C modification

Identifiers

PMID41417568
PMCPMC12955885

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.