Exosomes derived from FN14-overexpressing BMSCs activate the NF-κB signaling pathway to induce PANoptosis in osteosarcoma.

Despite advances in treatment, the prognosis of osteosarcoma (OS) patients is unsatisfactory, and searching for possible targets is substantial. Fibroblast growth factor inducible type 14 (FN14), a plasma membrane protein, is involved in wound healing, angiogenesis, proliferation, apoptosis, and inflammation. However, its implication in OS development and progression has not been completely characterized. Herein, we explored the cell-to-cell communication of bone marrow mesenchymal stem cells (BMSCs) and OS cells mediated by FN14 in the tumor microenvironment of OS. To assess the interplay between FN14 expression levels and patient survival, FN14 expression was measured in both normal and OS tissues. The FN14 overexpressing BMSCs (OE) were constructed using lentivirus, and exosomes (EXO) were extracted. The uptake of FN14-containing EXO by OS cells was analyzed via flow cytometry and in vivo fluorescence imaging. In addition, high-throughput sequencing was performed to analyze the mechanisms by which EXO inhibits OS cell growth. Finally, the therapeutic effect of OE-EXO was evaluated in a mouse model of OS xenografts. The results showcased reduced FN14 expression in human and mouse OS tissues, suggesting its role may be involved in the malignant progression of OS. The FN14 expression was higher in BMSCs relative to OS cells, and FN14 was secreted and excreted by EXO. The OS cell progression was suppressed after the uptake of FN14-derived EXO from BMSCs. In addition, RNA sequencing revealed that FN14 in EXO activated NF-κB signaling, triggering PANoptosis in OS cells. In vivo, OE-EXO injection inhibited tumor growth in OS xenografts and significantly improved the long-term survival of mice. Our findings suggest that FN14 carried by EXO from BMSCs activates the NF-κB pathway to trigger PANoptosis in OS cells, providing a potential therapeutic strategy to inhibit OS progression.