Clinical and molecular hepatology · 2026
HKDC1-mediated polyamine rewiring drives lenvatinib resistance and immune escape in hepatocellular carcinoma.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Chen Shiping, Wang Biao, Zhang Yang, Quan Bing, Shao Yujie, Zhu Guiqi, Cai Jialiang, Zhang Peiling, Song Lina, Wan Jinglei, Yang Yi, Du Junxian, Cai Yufan, Dai Zhi
Аннотация
BACKGROUND/AIMS: Lenvatinib 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.
METHODS: We 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.
RESULTS: HKDC1, 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.
CONCLUSIONS: A 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.
METHODS: We 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.
RESULTS: HKDC1, 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.
CONCLUSIONS: A 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.