biostudies-literatureUnknown13Niu X<h4>Background</h4>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.<h4>Materials and methods</h4>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 cellFrontiers in cell and developmental biology1620648https://www.ebi.ac.uk/biostudies/studies/S-EPMC12443774biostudies-literatureMulti-transcriptomics analysis of ferroptosis related genes reveals CAFs exosomal COX4I2 as a novel therapeutic target in osteosarcoma.PMC12443774Li ZTian WZhang XNiu XfalseMulti-transcriptomics analysis of ferroptosis related genes reveals CAFs exosomal COX4I2 as a novel therapeutic target in osteosarcoma.<h4>Background</h4>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.<h4>Materials and methods</h4>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 cell2025-01-01T00:00:00Z20252026-07-15T06:51:35.391Z2026-06-30T03:27:21.52ZS-EPMC124437744097789110.3389/fcell.2025.1620648