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Hepatocellular carcinoma (HCC) remains the most common primary liver cancer, with a high incidence and mortality rate. Remarkable progress has been made in cancer treatment in recent years; however, most patients with HCC still receive limited benefits from current treatment options. Therefore, there is an urgent need to explore novel and effective therapeutic strategies. Here, a novel combination therapy consisting of the calcineurin inhibitor cyclosporine A (CsA) and the flavone-naphthalimide-polyamine derivative 6c was identified. The combination of CsA and 6c inhibited cell viability and colony formation and induced GSDME-dependent pyroptosis. Mechanistically, RNA sequencing revealed that CsA and 6c synergistically activated the RIG-I-like receptor (RLR) signaling pathway. Moreover, the combination of CsA and 6c promoted RIG-I and MDA5 expression, TBK1 and IRF3 phosphorylation, and downstream target gene expression. RIG-I deletion attenuated the combination treatment-induced inhibition of cell growth, pyroptosis, and expression of IFN-stimulated genes (ISGs). Furthermore, combination treatment induced the downregulation of LDHA expression, leading to increased reactive oxygen species (ROS) generation. LDHA overexpression and ROS removal reversed the inhibitory effect of the combination treatment on HCC. Finally, combination of CsA and 6c suppressed tumor growth and pulmonary metastasis in vivo. Overall, our study suggests a novel synergistic treatment combination with a comprehensive mechanistic exploration, demonstrating that it is a promising strategy for HCC treatment via targeting RIG-I-like receptor signaling.