circZNF148 Drives Glucose Metabolism Reprogramming to Enhance Metastasis and Immune Evasion via HK1 Stabilization in Triple‐Negative Breast Cancer
4 affiliations
- 1Department of Breast Surgery General Surgery Qilu Hospital of Shandong University Jinan Shandong People's Republic of China
- 2Biological Resource Center Qilu Hospital of Shandong University Jinan Shandong People's Republic of China
- 3Department of Breast Surgery General Surgery The Affiliated Taian City Central Hospital of Qingdao University Taian Shandong People's Republic of China
- 4Research Institute of Breast Cancer Shandong University Jinan Shandong People's Republic of China
Abstract
Breast cancer is the leading malignancy among women worldwide, with triple‐negative breast cancer (TNBC) representing the most aggressive subtype. Accumulating evidence highlights glucose metabolism reprogramming as a critical driver of TNBC progression and immune evasion, yet the underlying molecular mechanism remains poorly defined. Using circRNA sequencing in both glucose metabolism‐stressed TNBC cells and lung metastasis models, we identified circZNF148 as a consistently upregulated circular RNA that promotes tumor progression and immune evasion by enhancing glycolysis. Mechanistically, circZNF148 scaffolds the interaction between hexokinase 1 (HK1) and the deubiquitinase adaptor ADRM1, suppressing K11‐linked ubiquitination and proteasomal degradation of HK1, thereby stabilizing the enzyme and sustaining glycolytic flux. Elevated lactate production subsequently impairs CD8+ T cell function, reducing IFN‐γ and TNF‐α secretion, diminishing cytotoxicity, and promoting exhaustion. Concurrently, increased intracellular lactate drives lysine lactylation of PD‐L1, which enhances its protein stability and membrane localization, thus linking metabolic state to immune checkpoint regulation. Clinically, circZNF148 is significantly upregulated in TNBC tissues, correlating with advanced stage and poor prognosis. Collectively, our findings establish the circZNF148‐HK1‐lactate axis as a critical mediator of metabolic adaptation and immune evasion in TNBC. Targeting this pathway offers a promising strategy to overcome therapeutic resistance and improve outcomes in TNBC.
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BibTeX
@article{jin2026circznf148,
title = {{circZNF148 Drives Glucose Metabolism Reprogramming to Enhance Metastasis and Immune Evasion via HK1 Stabilization in Triple‐Negative Breast Cancer}},
author = {Yuhan Jin and Wenjing Zhao and Lei Wang and Jianing Wang and Keying Zhao and Dan Luo and Yifei Wang and Yuxia Yang and Jingze Yang and Yaming Li and Tong Chen and Dianwen Han and Zekun Wang and Xiaoyan Li and Bing Chen and Lijuan Wang and Yiran Liang and Qifeng Yang},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77030},
url = {https://doi.org/10.1002/advs.77030},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - circZNF148 Drives Glucose Metabolism Reprogramming to Enhance Metastasis and Immune Evasion via HK1 Stabilization in Triple‐Negative Breast Cancer
AU - Yuhan Jin
AU - Wenjing Zhao
AU - Lei Wang
AU - Jianing Wang
AU - Keying Zhao
AU - Dan Luo
AU - Yifei Wang
AU - Yuxia Yang
AU - Jingze Yang
AU - Yaming Li
AU - Tong Chen
AU - Dianwen Han
AU - Zekun Wang
AU - Xiaoyan Li
AU - Bing Chen
AU - Lijuan Wang
AU - Yiran Liang
AU - Qifeng Yang
PY - 2026
DA - 2026/08/07
JO - Advanced Science
DO - 10.1002/advs.77030
UR - https://doi.org/10.1002/advs.77030
AB - Breast cancer is the leading malignancy among women worldwide, with triple‐negative breast cancer (TNBC) representing the most aggressive subtype. Accumulating evidence highlights glucose metabolism reprogramming as a critical driver of TNBC progression and immune evasion, yet the underlying molecular mechanism remains poorly defined. Using circRNA sequencing in both glucose metabolism‐stressed TNBC cells and lung metastasis models, we identified circZNF148 as a consistently upregulated circular RNA that promotes tumor progression and immune evasion by enhancing glycolysis. Mechanistically, circZNF148 scaffolds the interaction between hexokinase 1 (HK1) and the deubiquitinase adaptor ADRM1, suppressing K11‐linked ubiquitination and proteasomal degradation of HK1, thereby stabilizing the enzyme and sustaining glycolytic flux. Elevated lactate production subsequently impairs CD8+ T cell function, reducing IFN‐γ and TNF‐α secretion, diminishing cytotoxicity, and promoting exhaustion. Concurrently, increased intracellular lactate drives lysine lactylation of PD‐L1, which enhances its protein stability and membrane localization, thus linking metabolic state to immune checkpoint regulation. Clinically, circZNF148 is significantly upregulated in TNBC tissues, correlating with advanced stage and poor prognosis. Collectively, our findings establish the circZNF148‐HK1‐lactate axis as a critical mediator of metabolic adaptation and immune evasion in TNBC. Targeting this pathway offers a promising strategy to overcome therapeutic resistance and improve outcomes in TNBC.
SN - 2198-3844
ER -