PEA15 promotes osteosarcoma progression and cisplatin resistance by modulating autophagy through the FABP3-TNF signaling axis

Osteosarcoma (OS), a primary malignant bone tumor, is characterized by resistance to chemotherapeutic agents such as cisplatin (DDP), posing a major obstacle to effective treatment. Tumor cells often exploit autophagy to survive chemotherapeutic stress, which contributes to this resistance. Using weighted gene co-expression network analysis (WGCNA), this study screened for autophagy-related genes associated with OS prognosis and identified PEA15 as a key indicator of poor outcomes. Through gene knockdown and overexpression experiments in OS cell lines and xenograft models, we found that PEA15 promotes tumor progression. Mechanistically, RNA sequencing revealed that PEA15 inhibits autophagy and apoptosis by modulating the downstream target FABP3 and the associated TNF signaling pathway. Notably, silencing PEA15 in resistant OS cells enhanced their sensitivity to cisplatin by activating autophagy. These findings identify the PEA15-FABP3-TNF signaling axis as a key pathway regulating chemoresistance in OS, suggesting that targeting PEA15 could be a promising therapeutic strategy to improve patient outcomes.