GBP1 inhibits osteosarcoma progression by regulating DDX17 protein stability via HSPA8

Osteosarcoma (OS) stands as the preeminent primary malignant bone tumor, with its 5-year survival rate persistently lingering at 60%-70%. This therapeutic standstill is predominantly due to the shortage of sensitive early diagnostic markers and precise targeted treatment strategies. Guanylate-binding protein 1 (GBP1), a GTPase induced by interferons, serves as a tumor suppressor in multiple cancer types, yet its function and molecular mechanism in OS have remained uninvestigated. Our research reveals that GBP1 hinders OS tumor formation by promoting HSPA8-dependent ubiquitin-proteasome degradation of the DEAD-box RNA helicase 17 (DDX17) protein. Functional assays demonstrate that overexpression of GBP1 powerfully suppresses the proliferation, migration, and invasion of OS cells in vitro, and inhibits tumor growth in nude mouse xenograft models. Mechanistically, GBP1 forms a ternary complex with HSPA8 and DDX17, thereby enhancing the ubiquitination and proteasomal degradation of DDX17. Notably, overexpression of DDX17 counteracts the growth-inhibiting effects of GBP1, confirming its role as a crucial downstream effector. Clinical analyses show that GBP1 expression is markedly reduced in OS tissues, with a strong inverse correlation found between GBP1 levels and poor patient prognosis. These findings afford fresh perspectives on the biological processes driving OS progression and identify GBP1 as a potential therapeutic target for OS.