Metabolic reprogramming promotes AR-V7 splicing via SRSF2 lactylation in castration-resistant prostate cancer

  • Acta Biochim Biophys Sin (Shanghai). 2026 Apr 30;Vol.(1):fpage-lpage. doi: 10.3724/abbs.2026072.
Wenkai Zhu  1  2  3 ,  Jingran Xu  2 ,  Jesur Batur  2 ,  Zhenda Wang  4 ,  Xin An  2 ,  Xuan Yang  2 ,  Mierxiati Abudurexiti  4 ,  Dingwei Ye  3 ,  Fei Xiao  2  5  6  7  8
Affiliations
  • 1. The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
  • 2. Kashi Guangdong Institute of Science and Technology, The First People's Hospital of Kashi, Kashi 844000, China.
  • 3. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
  • 4. Department of Urology, Pudong Gongli Hospital, Shanghai University of Medicine & Health Sciences, Shanghai 200135, China.
  • 5. Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
  • 6. Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
  • 7. Guangdong-Hong Kong-Macao University Joint of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
  • 8. State Key Laboratory of Anti-Infective Drug Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 519000, China.
PMID: 42178282 DOI: 10.3724/abbs.2026072
Abstract

Metabolic alterations are a hallmark of Cancer, yet their direct influence on oncogenic splicing remains unclear. This study demonstrates that castration-resistant prostate Cancer (CRPC) exhibits enhanced glycolysis compared to hormone-sensitive disease, resulting in elevated lactate and increased global protein lactylation. Lactylomic profiling identifies the splicing factor SRSF2 as a key target, modified at a conserved lysine (K36). SRSF2 lactylation competes with ubiquitination, thereby stabilizing the protein and enabling it to promote the alternative splicing of Androgen Receptor (AR) pre-mRNA into the AR-V7 variant, a major driver of CRPC development. Functional assays confirm that both LDHA and SRSF2 are critical for CRPC cell proliferation, migration, and tumor growth, and their high expression correlates with poor patient prognosis. Our work establishes a direct mechanistic link between glycolysis and oncogenic splicing via protein lactylation, nominating the LDHA/SRSF2/AR-V7 axis as a therapeutic target.

Keywords
AR-V7; CRPC; glycolysis; lactylation.
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