OTULIN confers cisplatin resistance in osteosarcoma by mediating GPX4 protein homeostasis to evade the mitochondrial apoptotic pathway

Abstract Background Osteosarcoma (OS), the most prevalent primary malignant bone tumor in children and adolescents, arises from bone-forming mesenchymal cells. Despite advancements in surgical resection and neoadjuvant chemotherapy (cisplatin, doxorubicin, and methotrexate), chemotherapy resistance remains a significant challenge, leading to poor survival rates in patients with metastatic or recurrent OS. Methods In this study, we focused on the role of OTULIN, a key linear deubiquitinating enzyme, in OS chemoresistance. In addition, mechanistic investigations were carried out to identify potential downstream targets of OTULIN involved in cisplatin resistance. Results Our results demonstrated that OTULIN expression was significantly upregulated in OS tissues and cell lines following cisplatin treatment but not in response to doxorubicin or methotrexate. High OTULIN expression was associated with reduced survival in sarcoma patients. Furthermore, immunohistochemical analysis of prechemotherapy and postchemotherapy OS tissues revealed increased OTULIN expression in postchemotherapy samples. In vitro results demonstrated that OTULIN plays a critical role in mediating cisplatin resistance in OS. Mechanistically, GPX4 could be a downstream target of OTULIN, conferring cisplatin resistance to OS by blocking the mitochondrial apoptotic pathway but not ferroptosis. Specifically, OTULIN prevents the proteasomal degradation of GPX4 by reducing its ubiquitin level, thereby conferring resistance to cisplatin in OS cells. Conclusion This study highlights the importance of OTULIN in OS chemoresistance and provides a promising approach for targeting the OTULIN-GPX4 axis to improve the prognosis of OS patients. Our findings offer new insights into the molecular mechanisms underlying OS chemoresistance and suggest potential therapeutic targets for future clinical interventions.