Propofol inhibits glioma growth by blocking the formation of the NF-κB/LGI4 feedback loop to activate TP53 self-transcription

• Propofol inhibits the transcription of the LGI4 gene by blocking the NF-κB signaling pathway. • LGI4 interacts with the p53 protein to inhibit its nuclear translocation, thereby suppressing its autoregulation of transcription. • LGI4 amplifies the NF-κB signaling pathway by blocking IKIP. • Propofol disrupts the NF-κB/LGI4 loop, thereby upregulating p53. Accumulating evidence has clarified the anti-cancer function of propofol (PPF) in glioma. However, the underlying regulatory mechanism still remains not fully understood. Our current study screens out a novel gene-leucine-rich glioma-inactivated 4 (LGI4), as a target molecule of PPF, and shows that 10 μg/ml of PPF (a clinically relevant concentration commonly used in multiple previous studies) suppresses the NF-κB signaling pathway to inhibit LGI4 transcription in glioma cells. Clinically, the expression of LGI4 is upregulated in glioma tissues, and its high expression correlates with unfavorable prognosis. Functionally and mechanically, LGI4 promotes tumor growth through blocking TP53 self-transcription by binding to p53 and hindering its nuclear import. Significantly, LGI4 is not only transcriptionally activated by the NF-κB signaling pathway but also feedback activates NF-κB signaling by inhibiting the interaction of IKIP with the IKKα/IKKβ/NEMO complex. Importantly, PPF treatment can break this positive feedback loop. Collectively, our findings uncover that PPF upregulates p53 expression by disrupting the NF-κB/LGI4 feedback loop, thereby inhibiting glioma growth, highlighting it is a potential therapeutic target for future glioma treatment.