Evidence map›Paper›PMID 40745342›Full record

ArticleHereditas2025

EPHX1 enhances drug resistance to regorafenib by activating the JAK/STAT signaling pathway in hepatocellular carcinoma cell lines.

Bin Xu, Xiangnan Liang, Wuguang Liu, BaiTong Wu, Qiuxiang Wang, Gong Kai, Chun Han, Binwen Sun, Bing Dong, Chengyong Dong and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Hereditas, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing 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

4 citing papers in PubMed.

  1. Article
  2. Synergistic mechanisms and clinical translation of regorafenib combination therapies.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026
    Review
  3. Review
  4. 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

11 authors.

Bin Xu *Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China.
Xiangnan Liang *Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China.
Wuguang Liu *Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China.
BaiTong WuNephrology Department, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116000, China.
Qiuxiang WangEngineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China.
Gong KaiEngineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China.
Chun HanEngineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China.
Binwen SunEngineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China.
Bing DongEngineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China. dongbing776288522@163.com.
Chengyong DongEngineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China. dongchengy@126.con.
Liming WangEngineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China. wangbcc259@163.com.

Funding

Dalian Medical Science Research Program 2312016Innovative Teams Project in Key Areas of Dalian 2021RT01Liaoning Province talent plan project YXMJ-JC-04National Natural Science Foundation of China 81972749Science and Technology Project of Liaoning 2021JH2/10300020the National Natural Science Foundation of China 82203888United Foundation for Dalian Institute of Chemical Physics. Chinese Academy of Sciences and the Second Hospital of Dalian Medical University DMU-2&DICP UN202301
6 · The paper itself

Abstract

backgroundRegorafenib serves as a second-line treatment for patients with advanced hepatocellular carcinoma (HCC). Microsomal epoxide hydrolase 1 (EPHX1) is closely associated with tumorigenesis and drug resistance. However, the relationship between EPHX1 and regorafenib resistance, as well as the underlying mechanisms in HCC, remains unclear.

objectiveTo investigate the role and mechanisms of EPHX1 in mediating regorafenib resistance in HCC.

methodsWe assessed the protein expression levels of EPHX1 in human HCC tissues and adjacent non-tumor tissues. Subsequently, we constructed HCC cell lines with EPHX1 overexpression and knockdown using lentiviral vectors and stimulated these cells with varying concentrations of regorafenib. We then measured cell proliferation and apoptosis using flow cytometry and Western blotting. Additionally, we established xenograft tumor models to explore the impact of EPHX1 on the in vivo efficacy of regorafenib. Furthermore, we employed digital gene expression sequencing (DGE-seq) to investigate and validate the specific molecular mechanisms by which EPHX1 mediates regorafenib resistance in HCC cells.

resultsWe found that EPHX1 protein levels were significantly higher in HCC tissues compared to adjacent non-tumor tissues. EPHX1 inhibited the effects of regorafenib on cell proliferation and apoptosis. Consistently, the efficacy of regorafenib was enhanced in vivo following EPHX1 knockdown. Moreover, KEGG pathway enrichment analysis of DGE-seq data indicated that the JAK/STAT signaling pathway is crucial for EPHX1-induced regorafenib resistance. Finally, EPHX1 suppressed regorafenib-induced inactivation of the JAK/STAT signaling pathway and blocking this pathway with HY-N1447 alleviated EPHX1-induced regorafenib resistance.

conclusionIn summary, we conclude that EPHX1 enhances regorafenib resistance in HCC by activating the JAK/STAT signaling pathway. Our findings suggest that EPHX1 is a key resistance-related gene, which has significant implications for the application of regorafenib in advanced HCC.

Indexed as

Carcinoma, HepatocellularDrug Resistance, NeoplasmEpoxide HydrolasesLiver NeoplasmsPhenylurea CompoundsPyridinesAnimalsAntineoplastic AgentsApoptosisCell Line, TumorCell ProliferationGene Expression Regulation, NeoplasticHumansJanus KinasesMiceSignal TransductionAntineoplastic AgentsEPHX1 protein, humanEpoxide HydrolasesJanus KinasesPhenylurea CompoundsPyridinesregorafenibSTAT Transcription FactorsDrug resistanceEPHX1Hepatocellular carcinomaJAK/STAT pathwayRegorafenib

Identifiers

PMID40745342
PMCPMC12315303

What Socratic holds

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LicenceCC BY
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Registered trials

None linked

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.