2. Academic Validation
  3. High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy

High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy

  • Cell Rep. 2025 Apr 22;44(4):115545. doi: 10.1016/j.celrep.2025.115545.
Zhuo Xing 1,  Tiejun Yang 2,  Xurui Li 2,  Haozhe Xu 1,  Yulong Hong 1,  Shuai Shao 1,  Tao Li 3,  Liefu Ye 3,  Yuan Li 4,  Xin Jin 5,  Yongbao Wei 6
Affiliations

Affiliations

  • 1 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
  • 2 The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
  • 3 Shengli Clinical Medical College of Fujian Medical University, Department of Urology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, No. 134, Dong Street, Fuzhou 350001, People's Republic of China.
  • 4 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. Electronic address: yuanlixy@csu.edu.cn.
  • 5 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; FuRong Laboratory, Changsha 410078, Hunan, China. Electronic address: jinxinxy2@csu.edu.cn.
  • 6 Shengli Clinical Medical College of Fujian Medical University, Department of Urology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, No. 134, Dong Street, Fuzhou 350001, People's Republic of China. Electronic address: wyb1287@fzu.edu.cn.
PMID: 40215164 DOI: 10.1016/j.celrep.2025.115545
Abstract

Hyperglycemia is a recognized risk factor for bladder Cancer (BC). Enfortumab vedotin (EV), the first NECTIN4-targeting antibody-drug conjugate, demonstrates promising clinical efficacy in patients with advanced BC. In this study, we show that EV treatment is less effective in BC patients with diabetes than in those with normoglycemia. The subsequent in vitro and in vivo experiments indicate that high glucose decreases the sensitivity of BC cells to EV. Mechanistically, lactate overproduction associated with high glucose promotes AARS1-mediated YTHDC1 lactylation and enhances RNF183-mediated YTHDC1 ubiquitination. Downregulated YTHDC1 reduces JUND mRNA stability in an m6A-dependent manner, subsequently decreasing NECTIN4 expression and EV responsiveness. Our study identifies a high-glucose-associated lactate-AARS1-YTHDC1-JUND-NECTIN4 axis that affects EV sensitivity in BC. Targeting this axis with JUND activators or β-alanine may offer therapeutic strategies to enhance the sensitivity of BC cells to EV.

Keywords

CP: Cancer; NECTIN4; YTHDC1; bladder cancer; enfortumab vedotin.

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