Open Access
ARTICLE
miR-512-3p/RPS6KA2 Axis Regulates Cisplatin Resistance in Ovarian Cancer via Autophagy and Ferroptosis
Jianfa Wu1,2,3, Huang Chen3, Sihong Wang1,2, Lei Peng1,2, Xiaoying Hu1,2, Zhou Liu1,2,*
1 Department of Gynecology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China
2 Department of Gynecology, Shanghai University of Medicine & Health Sciences, Shanghai, 201318, China
3 Department of Integrated Traditional Chinese and Western Medicine Clinical Practice, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
* Corresponding Author: Zhou Liu. Email: 
(This article belongs to the Special Issue: Identification of potential targets and biomarkers for cancers and the exploration of novel molecular mechanisms of tumorigenesis and metastasis)
Oncology Research https://doi.org/10.32604/or.2025.070542
Received 18 July 2025; Accepted 07 November 2025; Published online 04 December 2025
Abstract
Objectives: Ribosomal protein S6 kinase A2 (RPS6KA2) has been identified as a potential prognostic biomarker in several cancers, including breast cancer, glioblastoma, and prostate cancer. However, its functional significance in ovarian cancer is not well characterized. This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer, particularly in relation to cisplatin resistance. Methods: The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR, immunofluorescence staining, immunohistochemistry, and western blotting. Prognostic associations were conducted using the Kaplan-Meier Plotter database. Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity. Ferroptosis-related parameters, including intracellular iron content, glutathione (GSH) levels, reactive oxygen species (ROS) generation, and mitochondrial membrane potential, were measured to determine ferroptotic changes. In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents. Results: Using ovarian cancer cell lines and clinical tissue samples, we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts. Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance. Mechanistically, RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) signaling pathway, which in turn increased sensitivity to cisplatin. Additionally, RPS6KA2 facilitated ferroptosis, contributing to its tumor-suppressive function. miR-512-3p was identified as a negative regulator of RPS6KA2, driving cisplatin resistance through suppression of RPS6KA2 expression. In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models. Conclusion: These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.
Keywords
RPS6KA2; autophagy; ovarian cancer; ferroptosis; chemoresistance
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