Liang Hao-Yu, Luo Rong-Zhen, Deng Ru, Chen Shi-Lu, Liu Xuan, Yang Xia, Wei Li-Jun, Wei Zong-Qiang, Wu Li-Yan, Shen Hui-Min, Yun Jing-Ping, Liu Li-Li
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.
Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
Cell Death Differ. 2025 Apr 11. doi: 10.1038/s41418-025-01500-z.
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.
卵巢癌（OC）是一种影响女性的高致死性和难治性恶性肿瘤，铂耐药仍然是一个主要的临床难题。与其他OC亚型相比，卵巢透明细胞癌（OCCC）经常表现出更高的铂难治性，同时伴有糖原水平升高，这促进了透明细胞形态的形成，以及野生型p53。然而，这些因素在OCCC铂耐药中的作用尚不清楚。在此，我们研究了糖原是否促进OCCC对铂类药物的耐药性，并报告糖原合成中的限速酶GYS1在临床上与OCCC的不良预后和化疗耐药相关。机制上，p53通过上调RNF144a促进GYS1降解，而GYS1通过竞争性结合USP14诱导p53去泛素化和降解的逆转，形成一个正反馈回路。在铂应激下，积累的糖原通过p53/GYS1反馈回路被动员起来，这为活跃的NADPH产生提供能量，导致对二硫化物诱导的细胞死亡产生抗性，并增加OCCC中的铂耐药性。总体而言，我们的研究结果确定糖原是OCCC铂耐药的一个促成因素，并阐明了潜在机制，突出了关键的p53/GYS1正反馈回路。
