The polymerase 1 and transcript release factor (PTRF)-cytoplasmic phospholipase A2 (cPLA2) phospholipid remodeling pathway facilitates tumor proliferation in glioma. Nevertheless, blockade of this pathway leads to the excessive activation of oncogenic receptors on the plasma membrane and subsequent drug resistance. Here, CD26/dipeptidyl peptidase 4 (DPP4) was identified through screening of CRISPR/Cas9 libraries. Suppressing PTRF-cPLA2 signaling resulted in the activation of the epidermal growth factor receptor (EGFR) pathway through phosphatidylcholine and lysophosphatidylcholine remodeling, which ultimately increased DPP4 transcription. In turn, DPP4 interacted with EGFR and prevented its ubiquitination. Linagliptin, a DPP4 inhibitor, facilitated the degradation of EGFR by blocking its interaction with DPP4. When combined with the cPLA2 inhibitor AACOCF3, it exhibited synergistic effects and led to a decrease in energy metabolism in glioblastoma cells. Subsequent in vivo investigations provided further evidence of a synergistic impact of linagliptin by augmenting the sensitivity of AACOCF3 and strengthening the efficacy of temozolomide. DPP4 serves as a novel target and establishes a constructive feedback loop with EGFR. Linagliptin is a potent inhibitor that promotes EGFR degradation by blocking the DPP4-EGFR interaction. This study presents innovative approaches for treating glioma by combining linagliptin with AACOCF3 and temozolomide.

Objective:To analyze the prognostic value of the coagulation index in stereotactic radio surgery(SRS)for patients with non-small cell lung cancer(NSCLC)and brain metastases(BMS).Methods:We retrospectively analyzed clinical data from 512 patients diagnosed with NSCLC and BMS,who were treated with SRS at Tianjin Huanhu Hospital from October 2015 to September 2018.The overall survival(OS)and progression-free survival(PFS)rates were analyzed.The Cox model was employed to examine prognostic factors.Subsequently,the receiver operating characteristic(ROC)curve was constructed based on multi-factor analysis usin the Cox model.The area under the ROC curve(AUC)was used to assess the prognostic value of coagulation indexes in patients with NSCLC and BMS who underwent SRS.Results:In 1,2,3,and 4 years,PFS rates were 79.9%,69.9%,56.6%,and 43.2%,respectively,and OS rates were 93.4%,83.2%,69.9%,and 57.6%,respectively.Smoking and average fibrinogen(Fib)levels,prothrombin time(PT),and D-dimer(D-D)levels were correlated with a longer PFS(P<0.05).Av-erage activated partial thromboplastin time(APTT),Fib,and D-D levels were correlated with a longer OS(P<0.05).Smoking and mean Fib and D-D levels were significantly correlated with a longer PFS(P<0.05),while The average levels of Fib and D-D are each significantly associated with longer OS rates(P<0.05).The combined detection of Fib and D-D in predicting the prognosis of NSCLC patients with brain metastases undergoing SRS treatment shows a significantly higher AUC compared to the detection of Fib and D-D individually(P<0.05).Conclusions:Co-agulation indexes have a certain correlation with the prognosis of patients with NSCLC and BMS treated with SRS.Furthermore Fib and D-D are independent risk factors for the prognosis of these patients and can be used to assess their outcomes.The combined evaluation of the indexes provides a more ideal prognostic assessment.