Unveiling and validation of a disulfidptosis determined prognostic model for osteosarcoma: new insights from prognosis to immunotherapy and chemotherapy

Objectives: Disulfidptosis, a novel form of cell death, has been reported to the be result of high levels of SLC7A11 protein after glucose starvation that led to cell death. In this study, we aimed to illustrate the association between disulfidptosis and osteosarcoma. Methods: Patients were collected from TARGET-OS and GSE21257, with a sequence matrix and clinical features. A total of 77 disulfidptosis genes were collected from the literature. A disulfidptosis-related prognostic signature (DSPR) was constructed using univariate Cox analysis, LASSO regression, and risk score computation. Nomograms were established by integrating independent prognostic factors and DSPR signatures. The Student' t-test or Mann-Whitney U test was used to compare between the two groups. The Log-rank test, univariate and multivariate Cox regression was performed for survival analysis. Results: A total of three distinct subtypes (C1, C2, and C3) with varying overall survival prognoses were identified. Comparison between C1 and C3 subtypes revealed 56 differentially-expressed genes, with six genes linked to prognosis. Using LASSO regression, a DSPR signature was constructed, which served as an independent prognostic indicator [hazard ratio (HR)=4.370, 95 % confidence interval (CI): 1.837-10.388, p<0.001], and further validated in an external GSE21257 cohort (HR=4.000, 95 % CI: 1.517-10.183, p=0.004). Nomogram incorporating clinical factors and DSPR signatures showed high predictive accuracy, with AUC values of 0.952 at 1-year, 0.890 at 2-year, and 0.873 at 3-year follow-up. Personalized therapy prediction indicated that low-point patients benefited more from anti-PD-1 immunotherapy, while for high-point patients, chemotherapy was a better treatment option. Conclusions: In this study, we identified disulfidptosis-associated genes and unraveled their roles in osteosarcoma prognosis, constructed a prognostic signature, and provided guidance for personalized treatment strategies.