Rapid Transcriptional Downregulation of PD-L1 by Sudachitin, a Polymethoxyflavone, in Glioblastoma Cells: A Class I HDAC-Dependent and Canonical Signaling-Independent Mechanism

Sudachitin, a polymethoxyflavone found in the peel of the Japanese citrus sudachi, has been reported to possess anti-cancer activity and the ability to modulate immune responses. Given its diverse pharmacological properties, expanding its application to malignant tumors of the central nervous system (CNS) represents a compelling therapeutic strategy. Furthermore, it has been suggested that sudachitin can cross the blood–brain barrier. Given these diverse pharmacological properties, extending its application to malignant tumors of the CNS represents an attractive therapeutic strategy. In various types of cancer, the expression of PD-L1 (programmed death-ligand 1) promotes immune evasion. In this study, we evaluated the effect of sudachitin on PD-L1 expression in human A172 glioblastoma cells. Sudachitin significantly suppressed PD-L1 levels. Although the major signaling pathways regulating PD-L1 include MEK, JAK, and NF-κB, pharmacological inhibition of these pathways failed to rescue the suppression of PD-L1 expression induced by sudachitin. In contrast, the broad-spectrum HDAC inhibitor trichostatin A moderately attenuated this suppression. Notably, the Class I-selective inhibitor mocetinostat (predominantly targeting HDAC1/2) fully restored PD-L1 expression to control levels. However, sirtuin modulators had no impact. These results show that sudachitin suppresses PD-L1 expression through a Class I HDAC-dependent mechanism. Overall, sudachitin represents a promising plant-derived immunomodulator for targeting immune checkpoints in brain tumors.