DDX17-mediated raptor-dependent mTORC1 activation links autophagy inhibition and metabolic compensation in HCC development.

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with an increasing global incidence and mortality. Dysregulated gene expression drives uncontrolled proliferation and metastasis, contributing to poor patient survival despite therapeutic advances. The DEAD-box RNA helicase DDX17 has been implicated in tumorigenesis, but its functional role and underlying mechanisms in HCC remain incompletely defined. Here, we found that DDX17 drives HCC tumorigenesis via a novel mechanism involving direct binding to Raptor, a core component of the mTORC1 complex, thereby activating mTORC1 signaling and inhibiting autophagy, as evidenced by reduced autophagosome formation and a decreased LC3-II/LC3-I ratio. Moreover, DDX17 unwinds the RNA G-quadruplex (rG4) structure in the Raptor 3′ untranslated region (3′ UTR), enhancing its translation and establishing Raptor as an rG4-dependent oncogenic target. Combined DDX17 knockdown and rapamycin treatment synergistically suppressed proliferation and induced autophagy. Additionally, DDX17 inhibition reshaped tumor cell metabolism by decreasing extracellular acidification and promoting lipid droplet accumulation following autophagy induction, highlighting its role in metabolic adaptation. These findings suggest that DDX17 promotes HCC progression by unwinding the rG4 motif in Raptor mRNA to enhance translation, activating mTORC1 signaling, and suppressing autophagy. Hence, co-targeting DDX17 and mTORC1 produces strong synergistic antitumor effects, revealing a promising therapeutic strategy for HCC.