2. Academic Validation
  3. Glycogen stores mediated by the p53-GYS1 feedback circuit engenders platinum resistance in ovarian clear cell carcinoma

Glycogen stores mediated by the p53-GYS1 feedback circuit engenders platinum resistance in ovarian clear cell carcinoma

  • Cell Death Differ. 2025 Apr 11. doi: 10.1038/s41418-025-01500-z.
Hao-Yu Liang # 1 2,  Rong-Zhen Luo # 1 2,  Ru Deng # 1 2,  Shi-Lu Chen # 1 2,  Xuan Liu 1 2,  Xia Yang 1 2,  Li-Jun Wei 1 2,  Zong-Qiang Wei 1 2,  Li-Yan Wu 1 2,  Hui-Min Shen 3,  Jing-Ping Yun 4 5,  Li-Li Liu 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
  • 2 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
  • 3 Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China. huimin_shen@126.com.
  • 4 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. yunjp@sysucc.org.cn.
  • 5 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. yunjp@sysucc.org.cn.
  • 6 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. liulil@sysucc.org.cn.
  • 7 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. liulil@sysucc.org.cn.
  • # Contributed equally.
PMID: 40210982 DOI: 10.1038/s41418-025-01500-z
Abstract

Ovarian Cancer (OC) is a highly fatal and refractory malignancy affecting women, and platinum resistance remains a major clinical dilemma. Compared with Other OC subtypes, ovarian clear cell carcinoma (OCCC) frequently exhibits increased platinum refractoriness, accompanied by increased glycogen levels, which promotes clear-cell morphology, and wild-type p53. However, the roles of these factors in platinum resistance of OCCC are unclear. Here, we investigated whether glycogen promotes OCCC resistance to platinum agents and reported that GYS1, a rate-limiting enzyme in glycogen synthesis, is clinically associated with poor prognosis and chemoresistance in OCCC. Mechanistically, p53 promotes GYS1 breakdown via the upregulation of RNF144a, whereas GYS1 induces the reversal of p53 ubiquitination and degradation by competitively binding to USP14, forming a positive feedback circuit. Under platinum stress, the accumulated glycogen is mobilized by the p53/GYS1 feedback circuit, which fuels energetic NADPH production, resulting in resistance to Disulfidptosis and increased platinum resistance in OCCC. Collectively, our findings identify glycogen as a contributor to OCCC platinum resistance and elucidate the underlying mechanisms, highlighting a crucial p53/GYS1 positive feedback loop.

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