DPP9 Expression in a PDTX Model of Undifferentiated Pleomorphic Sarcoma Reduced Mitochondrial Damage-Induced Ferroptosis for Diagnosis and Guidance for Individualized Clinical Treatment.

This study aims to screen for and target DPP9 expression in patient-derived tumor xenografts (PDTX) of Undifferentiated Pleomorphic Sarcoma (UPS) to advance personalized therapeutic strategies. We found that DPP9 mRNA expression is significantly upregulated in UPS patients. Single-cell RNA sequencing (scRNA-seq) further confirmed elevated DPP9 levels within the UPS tumor microenvironment. Functional studies demonstrated that shRNA-mediated knockdown of DPP9 suppressed tumor growth in UPS mouse models. Mechanistically, DPP9 promotes UPS cell proliferation by inhibiting mitochondria-dependent ferroptosis. Specifically, DPP9 reduces intracellular reactive oxygen species (ROS) accumulation and confers resistance to ferroptosis. Conversely, DPP9 downregulation induces ferroptosis by enhancing ROS production and mitochondrial dysfunction. Moreover, N6-methyladenosine (m6A) methylation enhances DPP9 mRNA stability in UPS, contributing to its overexpression. DPP9 also activates the NRF2 signaling axis by suppressing KEAP1-mediated ubiquitination and subsequent degradation of NRF2. This stabilization of NRF2 underlies DPP9's ability to inhibit mitochondria-dependent ferroptosis. Collectively, our findings identify DPP9 as a critical regulator of ferroptosis resistance in UPS and suggest that targeting DPP9 may represent a promising therapeutic strategy-not only for UPS, but potentially for other malignancies driven by dysregulated ferroptosis.