Evidence map›Paper›PMID 41812646›Full record

ArticleClinical and molecular hepatology2026

HKDC1-mediated polyamine rewiring drives lenvatinib resistance and immune escape in hepatocellular carcinoma.

Shiping Chen, Biao Wang, Yang Zhang, Bing Quan, Yujie Shao, Guiqi Zhu, Jialiang Cai, Peiling Zhang, Lina Song, Jinglei Wan and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Clinical and molecular hepatology, 2026. 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

14 authors.

Shiping Chen *Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
Biao Wang *Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
Yang Zhang *Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
Bing QuanLiver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
Yujie ShaoLiver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
Guiqi ZhuLiver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
Jialiang CaiLiver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
Peiling ZhangLiver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
Lina SongLiver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
Jinglei WanLiver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
Yi YangDepartment of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
Junxian DuDepartment of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Yufan CaiDepartment of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Zhi DaiLiver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China. dai.zhi@zs-hospital.sh.cn.

Funding

Beijing Bethune Charitable Foundation ZLZX019National Natural Science Foundation of China 82072670National Natural Science Foundation of China 82372946Shanghai Municipal Science and Technology Commission 21Y21900100
6 · The paper itself

Abstract

BACKGROUND/

aimsLenvatinib resistance and immune exclusion limit outcomes in hepatocellular carcinoma (HCC). We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and programmed cell death protein 1 (PD-1) blockade.

methodsWe established lenvatinib-sensitive/lenvatinib-resistant (LS/LR) HCC models and employed multi-omics (proteomics/RNA-seq), chromatin immunoprecipitation, luciferase, and RNA immunoprecipitation assays to map hexokinase domain containing protein 1 (HKDC1) regulation. Tumor immunity was profiled by scRNA-seq, multiplex fluorescent immunohistochemistry, and flow cytometry. Spermidine (SPD)+lenvatinib efficacy was tested in cell lines and patient-derived organoids/xenografts. Therapeutic effects were tested in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion and were analyzed a postoperative cohort (n=40) treated with lenvatinib+PD-1.

resultsHKDC1, upregulated in LR HCC, was transcriptionally activated by upstream stimulatory factor 1 (USF1) and promoted spermine synthase (SMS)-mediated polyamine rewiring. This impaired CD8+ T-cell metabolism, reversible by HKDC1 knockdown or SPD. SPD synergized with lenvatinib, triggering autophagy and suppressing tumor growth in vitro and in vivo. High HKDC1 predicted poor response and survival in patients receiving lenvatinib+aPD-1.

conclusionsA USF1/HKDC1/SMS axis couples polyamine metabolism to immune dysfunction and lenvatinib resistance. HKDC1 is a predictive biomarker and therapeutic node and supports polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.

Indexed as

Antineoplastic AgentsCarcinoma, HepatocellularDrug Resistance, NeoplasmLiver NeoplasmsPhenylurea CompoundsPolyaminesQuinolinesAnimalsCell Line, TumorHumansMiceSpermidineTumor EscapeAntineoplastic AgentslenvatinibPhenylurea CompoundsPolyaminesQuinolinesSpermidineaPD-1 immunotherapyCD8+ T cellsHepatocellular carcinomaLenvatinib resistancePolyamine metabolism

Identifiers

PMID41812646
PMCPMC13430367

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LicenceCC BY-NC
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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.