The biological function of GYS1 and p53 in ovarian clear cell carcinoma cell line.

Ovarian cancer (OC) is a highly fatal and refractory malignancy affecting women, with platinum resistance remaining a major clinical dilemma. Ovarian clear cell carcinoma (OCCC) frequently exhibits increased platinum refractoriness than the other OC subtypes, accompanied by heightened glycogen that engenders clear-cell morphology and wild-type p53. However, their roles in platinum resistance are unclear. Here, we investigated whether glycogen promotes OCCC platinum resistance, and found that GYS1 as a rate-limiting enzyme in glycogen synthesis is clinically associated with poor prognosis and chemoresistance in OCCC. GYS1 is a rate-limiting enzyme in glycogen synthesis, which is clinically associated with poor prognosis and chemoresistance in OCCC. Mechanistically, p53 promotes GYS1 breakdown via upregulating RNF144a, while GYS1 enhances reversed ubiquitination and degradation toward p53 by competitively bound to the USP14, forming a positive feedback circuit. Under platinum stress the accumulated glycogen is mobilized by p53/GYS1 feedback circuit, which fueling energetic NADPH production, hence gaining disulfidptosis invulnerability and increased platinum resistance in OCCC. Collectively, our study identifies glycogen as a contributor to OCCC platinum resistance and elucidates the underlying mechanisms, highlighting a crucial p53/GYS1 positive feedback loop.