Cancer-associated fibroblast exosomal miR-214-3p regulated by hnRNPA2B1 promotes cisplatin resistance by inhibiting ferroptosis

作者：Wen Tian, kai Chen, Luyue Deng, Wenli Ding, Xiaoying Niu, Feifei Feng, Peng Zhang · 发表于：International Journal of Surgery · 年份：2025 · DOI：10.1097/js9.0000000000003946 · 被引用次数：3 · 研究领域：Ferroptosis and cancer prognosis、Extracellular vesicles in disease、Cancer-related molecular mechanisms research

BACKGROUND: Cisplatin resistance continues to represent a significant clinical challenge in the treatment of osteosarcoma. Accumulating evidence suggests that cancer-associated fibroblast (CAF) play a pivotal role in shaping a chemotherapy-resistant tumor microenvironment through exosome-mediated intercellular communication. In this study, we identified hnRNPA2B1 as a critical RNA-binding protein involved in the regulation of exosomal miRNA sorting within CAF, thereby contributing to the development of cisplatin resistance in osteosarcoma. MATERIALS AND METHODS: Single-cell RNA sequencing was performed on cisplatin-sensitive samples and cisplatin-resistant samples. Expression levels of hnRNPA2B1 in CAF subsets were analyzed. Exosome secretion from CAF was quantified. RNA immunoprecipitation assays were used to assess hnRNPA2B1 binding to miR-214-3p. Functional assays were conducted by transferring CAF-derived exosomes to osteosarcoma cells, followed by evaluation of GPX4 expression, ferroptosis, and cisplatin sensitivity. GPX4 overexpression experiments were performed both in vitro and in vivo to assess its ability to reverse the effects of exosomal miR-214-3p. RESULTS: Single-cell RNA sequencing analysis demonstrated that CAF subpopulations exhibiting high expression levels of hnRNPA2B1 were predominantly present in cisplatin-resistant tumors. We further found that hnRNPA2B1 enhanced exosome secretion and facilitated the selective incorporation of miR-214-3p into exosomes by...