LACTB-Induced ERBB3 Degradation Inhibits Lipid Synthesis and Suppresses Glioma Growth

Abnormal lipid metabolism is a hallmark of cancer and represents a potential target for anti-cancer strategies. β-lactamase-like protein (LACTB) is a novel tumor suppressor; however, its biological functions and underlying mechanisms in glioma remain poorly understood. In this study, we demonstrate that LACTB suppresses glioma growth independent of its enzymatic activity. Through RNA sequencing and untargeted lipidomics analysis, we reveal that LACTB inhibits lipid synthesis in glioma cells. Mechanistically, LACTB downregulates ERBB3 and suppresses the PI3K/AKT/mTOR signaling pathway, thereby restraining tumor cell lipogenesis. Furthermore, we show that LACTB reduces ERBB3 protein stability by promoting its lysosomal degradation. Specifically, LACTB or S164I enhances the interaction between ERBB3 and Hsc70, facilitating ERBB3 degradation in the lysosome. Finally, we demonstrate that targeting the LACTB/ERBB3 axis significantly inhibits glioma growth in the mouse model. Our findings highlight the anti-tumor role of LACTB in glioma and identify the LACTB/ERBB3 axis as a potential therapeutic target for this malignancy.