SEPTIN7 Enhances Tumorgenesis and Therapeutic Resistance in Hepatocellular Carcinoma by Promoting FGFR4 Stabilization and Recycling

Abstract Hepatocellular carcinoma (HCC) is a highly lethal malignancy with rapid onset of drug resistance and high recurrence rate, partly driven by cancer stem cells (CSCs). In this study, we identified a small GTPases SEPTIN7 as a critical regulator of tumorigenesis and therapeutic resistance in HCC. SEPTIN7 was significantly upregulated in human HCC samples with high stemness scores and was positively associated with recurrence and poor prognosis. SEPTIN7 also promoted CSC self-renewal and conferred resistance to therapy in HCC cell lines and patient-derived organoids. Genetic knockout of Septin7 in hepatocytes suppressed HCC initiation and progression in both hydrodynamic tail vein injection (HTVI)- and diethylnitrosamine (DEN)-induced mouse models. Mechanistically, SEPTIN7 regulated the receptor tyrosine kinase FGFR4 via dual pathways, stabilizing FGR4 through inhibition of K48-linked ubiquitination at lysine 471 while simultaneously promoting RACK1-mediated phosphorylation at serine 440. These coordinated actions enhanced FGFR4 membrane recycling and downstream signaling, establishing a feedback loop that amplifies oncogenic output, promotes tumorigenesis, and drives therapeutic resistance. Disruption of this loop improved therapeutic efficacy in HCC by reducing FGFR4 stability and activity. Taken together, this study elucidates an unconventional SEPTIN7-FGFR4 regulatory network and provides a rationale for therapeutic strategies targeting this axis in the treatment of HCC.