Multi-transcriptomics analysis of ferroptosis related genes reveals CAFs exosomal COX4I2 as a novel therapeutic target in osteosarcoma

作者：Xiaoying Niu, Xinxin Zhang, Zhongyi Li, Wen Tian · 发表于：Frontiers in Cell and Developmental Biology · 年份：2025 · DOI：10.3389/fcell.2025.1620648 · 被引用次数：1 · 研究领域：Ferroptosis and cancer prognosis、FOXO transcription factor regulation、Clusterin in disease pathology

Background Osteosarcoma is a primary malignant tumor, characterized by its high incidence and recurrence rate in children and adolescents. Ferroptosis, an iron-dependent form of regulated cell death, has recently been recognized as a potential therapeutic vulnerability in cancer treatment. However, its prognostic significance and underlying regulatory mechanisms in osteosarcoma remain largely unexplored. Materials and methods We constructed a prognostic model based on 12 ferroptosis-related genes using LASSO regression and validated across independent GEO cohorts (GSE21257 and GSE39055). We identified hub genes via machine learning algorithms (SVM, RF, XGBoost, BORUTA) and single-cell RNA sequencing. The exosomal transfer of COX4I2 protein from CAFs to 143B osteosarcoma cells was evaluated by Western blot, confocal microscopy, and transmission electron microscopy. Ferroptosis indicators, including Fe 2+ , MDA, ACSL4, and ROS levels, were assessed in vitro . We performed tumorigenicity assays in vivo in nude mice to validate biological function. Results The ferroptosis-based risk model exhibited robust prognostic performance. We identified COX4I2 as a stromal hub gene, highly enriched in cancer-associated fibroblasts (CAFs). Functional experiments demonstrated that exosome-mediated delivery of COX4I2 suppressed ferroptosis in osteosarcoma cells and enhancd cell proliferation and mitochondrial integrity. Studies in vivo further revealed that overexpression of exosomal COX4I2 ma...