• RP11-439C15.4 is significantly downregulated in hepatocellular carcinoma (HCC) and its low expression correlates with poor patient prognosis.
• Overexpression of RP11-439C15.4 suppresses HCC cell proliferation, invasion, migration, and sorafenib resistance in vitro and in vivo.
• Mechanistically, RP11-439C15.4 binds to DHX9, promoting its ubiquitination and proteasomal degradation, thereby inhibiting HCC progression.
• The RP11-439C15.4/DHX9 axis represents a novel therapeutic target and potential biomarker for HCC diagnosis and treatment.