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.

Glioma is the most common malignant primary brain tumor in adults,characterized by rapid malignant progression,high recurrence rates,and high mortality.The main treatment methods are surgery followed by radiotherapy and chemotherapy.Temozolomide,as the first-line drug for glioma treatment,is exposed to increasingly severe issues with drug resistance,which significantly impacts the efficacy and prognosis for glioma patients.With advancements in molecular biomarker detection and the emergence of precision medicine,targeted and individualized treatment strategies for glioma patients are evolving rapidly.The discovery of new glioma biomarkers,such as long non-coding RNA HOTAIR(HOX antisense intergenic RNA),polymerase Ⅰ and transcript release factor(PTRF/Cavin1),and MET,along with the application of new technologies like computer-aided drug design(CADD),has ushered in a new era for the design and development of targeted drugs for glioma.Due to the heterogeneity of glioma,the effectiveness of single-target drugs is limited.In the future,a combination of physical,chemical,and biological interventions will be the breakthrough direction for glioma treatment.

Glioma is the most common malignant primary brain tumor in adults,characterized by rapid malignant progression,high recurrence rates,and high mortality.The main treatment methods are surgery followed by radiotherapy and chemotherapy.Temozolomide,as the first-line drug for glioma treatment,is exposed to increasingly severe issues with drug resistance,which significantly impacts the efficacy and prognosis for glioma patients.With advancements in molecular biomarker detection and the emergence of precision medicine,targeted and individualized treatment strategies for glioma patients are evolving rapidly.The discovery of new glioma biomarkers,such as long non-coding RNA HOTAIR(HOX antisense intergenic RNA),polymerase Ⅰ and transcript release factor(PTRF/Cavin1),and MET,along with the application of new technologies like computer-aided drug design(CADD),has ushered in a new era for the design and development of targeted drugs for glioma.Due to the heterogeneity of glioma,the effectiveness of single-target drugs is limited.In the future,a combination of physical,chemical,and biological interventions will be the breakthrough direction for glioma treatment.