Dual targeting of ACSS2 and ACLY by a novel inhibitor S8588 suppresses oncogenic lipogenesis and overcomes metabolic compensation in oral squamous cell carcinoma
6 affiliations
- 1Hunan Key Laboratory of Oral Health Research & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China
- 2Research Center for Molecular Medicine and Biomanufacturing, Hunan Province Key Laboratory of Basic and Applied Hematology, Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Xiangya School of Medicine, Central South University, Changsha, China
- 3National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Central South University, Changsha, China
- 4The Oncology Department of Xiangya Second Hospital, Central South University, Changsha, China
- 5The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China
- 6MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, University of South China, Hengyang, China
Abstract
Metabolic reprogramming, particularly enhanced lipid anabolism, is a hallmark of oral squamous cell carcinoma (OSCC), yet effective therapies targeting this process remain lacking. Here, we identify concurrent activation of acetyl-CoA synthetase 2 (ACSS2) and ATP-citrate lyase (ACLY) as a cooperative metabolic driver of OSCC progression. Whereas previous efforts have focused on single-enzyme inhibition, we show that ACSS2 and ACLY form a compensatory network that sustains lipid anabolism and drives OSCC progression, providing a rationale for their dual inhibition. Integrative transcriptomic and lipidomic analyses reveal a metabolically aggressive OSCC subset defined by concurrent ACSS2 and ACLY upregulation, which was associated with poor clinical outcomes. Dual inhibition of ACSS2 and ACLY depleted acetyl-CoA, suppressed lipogenesis, and impaired tumor growth in vitro and in vivo. We further identified S8588, a quinoxaline-based small molecule, as a dual-target degrader that induces ubiquitin–proteasome-dependent degradation of both ACSS2 and ACLY, thereby blocking OSCC proliferation. Mechanistically, S8588 directly binds key residues of both enzymes, promoting their proteasomal turnover. Supplementation with acetate and citrate reverses its anti-tumor effect, confirming acetyl-CoA depletion as the primary mechanism. Collectively, our findings establish ACSS2/ACLY co-activation as a therapeutic vulnerability in OSCC and nominate S8588 as a promising dual-target therapeutic to dismantle metabolic adaptability for improved treatment.
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BibTeX
@article{luo2026dual,
title = {{Dual targeting of ACSS2 and ACLY by a novel inhibitor S8588 suppresses oncogenic lipogenesis and overcomes metabolic compensation in oral squamous cell carcinoma}},
author = {Tiao Luo and Zhengnan Ming and Haixia Zhang and Zizheng Zou and Xiyuan Hu and Yekui Yin and Ying Wang and Zekun Zhou and Xin Bin and Jianjun Wu and Junli Luo and Zhiyong Luo and Zhangui Tang and Ousheng Liu},
journal = {International Journal of Oral Science},
year = {2026},
month = oct,
doi = {10.1038/s41368-026-00467-y},
url = {https://doi.org/10.1038/s41368-026-00467-y},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Dual targeting of ACSS2 and ACLY by a novel inhibitor S8588 suppresses oncogenic lipogenesis and overcomes metabolic compensation in oral squamous cell carcinoma
AU - Tiao Luo
AU - Zhengnan Ming
AU - Haixia Zhang
AU - Zizheng Zou
AU - Xiyuan Hu
AU - Yekui Yin
AU - Ying Wang
AU - Zekun Zhou
AU - Xin Bin
AU - Jianjun Wu
AU - Junli Luo
AU - Zhiyong Luo
AU - Zhangui Tang
AU - Ousheng Liu
PY - 2026
DA - 2026/10/31
JO - International Journal of Oral Science
DO - 10.1038/s41368-026-00467-y
UR - https://doi.org/10.1038/s41368-026-00467-y
AB - Metabolic reprogramming, particularly enhanced lipid anabolism, is a hallmark of oral squamous cell carcinoma (OSCC), yet effective therapies targeting this process remain lacking. Here, we identify concurrent activation of acetyl-CoA synthetase 2 (ACSS2) and ATP-citrate lyase (ACLY) as a cooperative metabolic driver of OSCC progression. Whereas previous efforts have focused on single-enzyme inhibition, we show that ACSS2 and ACLY form a compensatory network that sustains lipid anabolism and drives OSCC progression, providing a rationale for their dual inhibition. Integrative transcriptomic and lipidomic analyses reveal a metabolically aggressive OSCC subset defined by concurrent ACSS2 and ACLY upregulation, which was associated with poor clinical outcomes. Dual inhibition of ACSS2 and ACLY depleted acetyl-CoA, suppressed lipogenesis, and impaired tumor growth in vitro and in vivo. We further identified S8588, a quinoxaline-based small molecule, as a dual-target degrader that induces ubiquitin–proteasome-dependent degradation of both ACSS2 and ACLY, thereby blocking OSCC proliferation. Mechanistically, S8588 directly binds key residues of both enzymes, promoting their proteasomal turnover. Supplementation with acetate and citrate reverses its anti-tumor effect, confirming acetyl-CoA depletion as the primary mechanism. Collectively, our findings establish ACSS2/ACLY co-activation as a therapeutic vulnerability in OSCC and nominate S8588 as a promising dual-target therapeutic to dismantle metabolic adaptability for improved treatment.
SN - 1674-2818
SN - 2049-3169
ER -