Asah2 Represses the p53-Hmox1 Axis to Protect Myeloid-Derived Suppressor Cells from Ferroptosis.

摘要: Myeloid-derived suppressor cells (MDSCs) are immune suppressive that massively accumulate under pathological conditions to suppress T cell response. Dysregulated death contributes MDSC accumulation, but the molecular mechanism underlying this dysregulation is not fully understood. In study, we report neutral ceramidase (N-acylsphingosine amidohydrolase [ASAH2]) highly expressed in tumor-infiltrating MDSCs colon carcinoma and acts as an survival factor. To target ASAH2, performed docking based on human ASAH2 protein structure. Enzymatic inhibition analysis of identified hits determined NC06 inhibitor. Chemical nuclear magnetic resonance 7-chloro-2-(3-chloroanilino)pyrano[3,4-e][1,3]oxazine-4,5-dione. inhibits activity with IC50 10.16-25.91 μM for 18.6-30.2 mouse Asah2 proteins. induces a dose-dependent manner, ferroptosis decreased NC06-induced death. increases glutathione synthesis decreases lipid reactive oxygen species MDSCs. Gene expression profiling p53 pathway Inhibition increased stability upregulate Hmox1 production therapy reduces accumulation tumor-bearing mice, resulting activation CTLs suppression tumor growth vivo. Our data indicate protects from through destabilizing microenvironment. Targeting induce potentially effective cancer immunotherapy.