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STING inhibits the progression of esophageal squamous cell carcinoma by suppressing CPT1A-mediated fatty acid β-oxidation

Acta Pharmacologica Sinica volume 46, pages 2793–2807 (2025)Cite this article

Abstract

Esophageal squamous cell carcinoma (ESCC) is characterized by high aggressiveness and poor prognosis. Metabolic reprogramming is a hallmark of ESCC, with lipid metabolism frequently upregulated. It has been shown that lipid metabolism, particularly fatty acid β-oxidation (FAO), plays an essential role in energy homeostasis, membrane biosynthesis, and tumor progression. Stimulator of interferon genes (STING), a key innate immune signaling molecule, also acts as a metabolic checkpoint by inhibiting hexokinase 2, thereby limiting aerobic glycolysis and enhancing anti-tumor immune responses. In this study, we investigated the impact of STING on FAO and tumorigenesis in ESCC. We showed that the expression levels of STING were significantly reduced in ESCC compared to adjacent normal tissue. In the ESCC cell line KYSE-510, knockdown of STING significantly elevated lipid metabolites, decreased intracellular lipid droplets, and increased FAO products, whereas overexpression of STING inhibited ESCC cell proliferation and tumor progression by suppressing FAO. Targeted lipid metabolomic analyses revealed that STING interacted with carnitine palmitoyltransferase 1A (CPT1A), a key enzyme in FAO. STING promoted the ubiquitination and degradation of CPT1A by disrupting its interaction with USP15, a deubiquitinating enzyme. Treatment with the CPT1A inhibitor etomoxir (50 μM) reversed the increased FAO induced by STING depletion in KYSE-30 cells. In both in vitro and in vivo models, supplementation with palmitic acid rescued STING-induced growth inhibition, restoring tumor cell growth. In addition, STING knockout in 4-NQO-induced ESCC mice led to accelerated tumor progression, which could be mitigated by CPT1A inhibition. Our results suggest that reduced STING expression enhances FAO and promotes ESCC cell proliferation, implicating FAO suppression as a potential therapeutic strategy for ESCC.

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Fig. 1: STING is lowly expressed in ESCC.
Fig. 2: STING inhibits the proliferation of ESCC cells and tumors.
Fig. 3: STING attenuates fatty acid oxidation in ESCC.
Fig. 4: FAO supplementation reverses STING’s inhibition of ESCC cells and tumors.
Fig. 5: STING CDN-binding domain interacts with CPT1A.
Fig. 6: The expression of CPT1A in ESCC was up-regulated and negatively correlated with STING.
Fig. 7: STING promotes K48-linked ubiquitination of CPT1A by inhibiting the interaction between CPT1A and USP15.
Fig. 8: Inhibition of CPT1A suppresses STING-deficiency-induced ESCC progression.
Fig. 9

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Data availability

All data supporting the findings of this study are available within the manuscript and its supplementary information files.

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Acknowledgements

We thank scientists in the Xu Lab for their technical support and constructive discussions. This work was supported by the National Key Research and Development Program of China (2023YFE0109800), the National Natural Science Foundation of China (Nos. 82020108024, 82400658, and 82200596), the China Postdoctoral Science Foundation (No. 2022M721014) and the Scientific and Technological Research Project of Henan Province (No. 252102311069).

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  1. These authors contributed equally: Lei Zhang, Ling-jun Zhu.

Authors and Affiliations

  1. School of Life Sciences, Henan University, Kaifeng, 475001, China

    Lei Zhang, Ling-jun Zhu, Yuan Zhao, Xin-yuan Lei, Dan-hui Wu, Kai-yue He, Meng-jie Liu, Jing-yu Yang, Jin-rong Guo, Zhi-hao Jiang, Zhen-hua Yan, Zhi-xiang Xu & Yong-ping Jian

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Contributions

LZ wrote the manuscript and designed the study. LJZ, YZ, XYL, DHW, KYH, MJL, JYY, JRG, ZHJ, and ZHY performed the experiments. YPJ and ZXX contributed to the conception and writing. All authors read and approved the final manuscript.

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Correspondence to Zhi-xiang Xu or Yong-ping Jian.

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All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at Henan University, China, and complied with institutional guidelines. Experiments were conducted at the Laboratory Animal Center of Henan University.

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Zhang, L., Zhu, Lj., Zhao, Y. et al. STING inhibits the progression of esophageal squamous cell carcinoma by suppressing CPT1A-mediated fatty acid β-oxidation. Acta Pharmacol Sin 46, 2793–2807 (2025). https://doi.org/10.1038/s41401-025-01581-z

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