2. Academic Validation
  3. PDHA1-acetylation signaling suppresses cuproptosis to attenuate anti-androgen effect in prostate cancer

PDHA1-acetylation signaling suppresses cuproptosis to attenuate anti-androgen effect in prostate cancer

  • Cell Death Dis. 2026 Feb 23;17(1):243. doi: 10.1038/s41419-026-08462-1.
Ruilin Zhuang # 1 2 3,  Qianghua Zhou # 2,  Bisheng Cheng # 4,  Shirong Peng # 1 3,  Zhi Xiong 1 3,  Zhaoxiang Xie 1 3,  Weilong Lin 1 3,  Tong Su 1 3,  Zean Li 1 3,  Kai Yao 2,  Zhiming Wu 5,  Hai Huang 6 7 8 9,  Kaiwen Li 10 11 12
Affiliations

Affiliations

  • 1 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Department of Urology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
  • 3 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 4 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 5 Department of Urology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China. [email protected].
  • 6 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 7 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. [email protected].
  • 8 Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. [email protected].
  • 9 Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China. [email protected].
  • 10 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 11 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. [email protected].
  • 12 Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41730841 DOI: 10.1038/s41419-026-08462-1
Abstract

Acquired resistance to enzalutamide (Enz) presents a significant challenge in castration-resistant prostate Cancer (CRPC), and overcoming this resistance remains an unmet clinical need. Here, we identified Cuproptosis, a copper-dependent mechanism of regulated cell death, as a key driver of Enz resistance. Both in vitro and in vivo models demonstrated that pyruvate dehydrogenase E1 alpha subunit (PDHA1) serves as a critical modulator of Cuproptosis and Enz sensitivity. Mechanistically, PDHA1 increases intracellular acetyl-CoA, enhancing histone H3K27 acetylation and upregulating solute carrier family 7 member 11 (SLC7A11), which promotes cysteine uptake and glutathione (GSH) synthesis. Elevated GSH chelates intracellular copper, thereby suppressing Cuproptosis and reducing Enz efficacy. Targeting PDHA1 significantly restores Cuproptosis and sensitizes CRPC cells to Enz treatment. These findings underscore the potential of PDHA1 inhibition to counteract Enz resistance by reactivating Cuproptosis, offering a promising therapeutic approach for treating refractory prostate Cancer.

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