Comprehensive analysis of SQOR involvement in ferroptosis resistance of pancreatic ductal adenocarcinoma in hypoxic environments.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) exhibits higher hypoxia level than most solid tumors, and the presence of intratumoral hypoxia is associated with a poor prognosis. However, the identification of hypoxia levels based on pathological images, and the mechanisms regulating ferroptosis resistance, remain to be elucidated. The objective of this study was to construct a deep learning model to evaluate the hypoxia characteristics of PDAC and to explore the role of Sulfide quinone oxidoreductase (SQOR) in hypoxia-mediated ferroptosis resistance. METHODS: Multi-omics data were integrated to analyze the correlation between hypoxia score of PDAC, SQOR expression and prognosis, and ferroptosis resistance level. A deep learning model of Whole Slide Images (WSIs) were constructed to predict the hypoxia level of patients. In vitro hypoxia cell models, SQOR knockdown experiments and nude mouse xenograft models were used to verify the regulatory function of SQOR on ferroptosis. RESULTS: PDAC exhibited significantly higher hypoxia levels than normal tissues, correlating with reduced overall survival in patients. In slide level, our deep learning model can effectively identify PDAC hypoxia levels with good performance. SQOR was upregulated in tumor tissues and positively associated with both hypoxia score and ferroptosis resistance. SQOR promotes the malignant progression of PDAC in hypoxic environment by enhancing the resistance of tumor cells to ferroptosis. SQOR knockdown resulted in decreased cell viability, decreased migration ability and increased MDA level under hypoxic Ersatin induced conditions. Furthermore, SQOR inhibitor in combination with ferroptosis inducer has the potential to inhibit tumor growth in vivo in a synergistic manner. DISCUSSION: This study has established a hypoxia detection model of PDAC based on WSIs, providing a new tool for clinical evaluation. The study revealed a new mechanism of SQOR mediating ferroptosis resistance under hypoxia and provided a basis for targeted therapy.