Targeting the USP13–ACLY axis in tumor endothelial cells: Ginsenoside Rd suppresses pathological angiogenesis through metabolic-epigenetic reprogramming
4 affiliations
- 1Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- 2School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
- 3Department of Digestive Tumor Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
- 4Department of Colorectal Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
Abstract
ATP citrate lyase (ACLY) is a pivotal enzyme implicated in cancer cells’ aberrant survival and proliferation. However, its precise role in tumor endothelial cells (TECs) in tumor angiogenesis and malignant progression remains poorly defined. Our previous studies have identified a high distribution of ginsenoside Rd in TECs, yet the mechanism underlying its anti-angiogenic properties has not been elucidated. Here, we clarify the direct regulatory effects of ACLY in TECs and explain how Rd reprograms the ACLY metabolic pathway in TECs. Systemic Acly silencing in tumor models resulted in suppressed angiogenesis and tumor progression. Importantly, TEC-specific Acly knockdown directly disrupted pathological vascularization and exerted comparable inhibitory effects on tumor growth. Metabolomic profiling revealed that ginsenoside Rd reduced nuclear acetyl-coenzyme A (acetyl-CoA) levels by down-regulating ACLY expression, thereby inhibiting the transcription of angiogenesis-related factors through reduced acetylation of histone H3 (but not H4). Mechanistically, ginsenoside Rd promotes the ubiquitin-mediated degradation of ACLY by targeting and suppressing ubiquitin-specific peptidase 13 (USP13). This study not only establishes a mechanistic framework for the development of ACLY-centric therapeutic strategies to reprogram pathological vasculature but also identifies the natural compound Rd as a pharmacological modulator of TECs metabolism via targeting the USP13–ACLY axis.
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BibTeX
@article{li2026targeting,
title = {{Targeting the USP13–ACLY axis in tumor endothelial cells: Ginsenoside Rd suppresses pathological angiogenesis through metabolic-epigenetic reprogramming}},
author = {Haobin Li and Haocheng Deng and Jiali Liu and Qixiang Zhang and Lingge Cheng and Li Wan and Mengyuan Gao and Yujie Han and Xinping Wang and Xue Zhou and Sainan Peng and Lihua Shao and Guangji Wang and Chao Jiang and Chongjin Zhong and Fang Zhou},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = sep,
doi = {10.1016/j.apsb.2026.09.002},
url = {https://europepmc.org/article/PMC/PMC13729718},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Targeting the USP13–ACLY axis in tumor endothelial cells: Ginsenoside Rd suppresses pathological angiogenesis through metabolic-epigenetic reprogramming
AU - Haobin Li
AU - Haocheng Deng
AU - Jiali Liu
AU - Qixiang Zhang
AU - Lingge Cheng
AU - Li Wan
AU - Mengyuan Gao
AU - Yujie Han
AU - Xinping Wang
AU - Xue Zhou
AU - Sainan Peng
AU - Lihua Shao
AU - Guangji Wang
AU - Chao Jiang
AU - Chongjin Zhong
AU - Fang Zhou
PY - 2026
DA - 2026/09/05
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.09.002
UR - https://europepmc.org/article/PMC/PMC13729718
AB - ATP citrate lyase (ACLY) is a pivotal enzyme implicated in cancer cells’ aberrant survival and proliferation. However, its precise role in tumor endothelial cells (TECs) in tumor angiogenesis and malignant progression remains poorly defined. Our previous studies have identified a high distribution of ginsenoside Rd in TECs, yet the mechanism underlying its anti-angiogenic properties has not been elucidated. Here, we clarify the direct regulatory effects of ACLY in TECs and explain how Rd reprograms the ACLY metabolic pathway in TECs. Systemic Acly silencing in tumor models resulted in suppressed angiogenesis and tumor progression. Importantly, TEC-specific Acly knockdown directly disrupted pathological vascularization and exerted comparable inhibitory effects on tumor growth. Metabolomic profiling revealed that ginsenoside Rd reduced nuclear acetyl-coenzyme A (acetyl-CoA) levels by down-regulating ACLY expression, thereby inhibiting the transcription of angiogenesis-related factors through reduced acetylation of histone H3 (but not H4). Mechanistically, ginsenoside Rd promotes the ubiquitin-mediated degradation of ACLY by targeting and suppressing ubiquitin-specific peptidase 13 (USP13). This study not only establishes a mechanistic framework for the development of ACLY-centric therapeutic strategies to reprogram pathological vasculature but also identifies the natural compound Rd as a pharmacological modulator of TECs metabolism via targeting the USP13–ACLY axis.
SN - 2211-3835
SN - 2211-3843
ER -