NF-κB signaling in hepatocellular carcinoma: Mechanisms of tumor progression, immune evasion, and therapeutic resistance

• NF-κB signaling in HCC is pathologically stabilized rather than transiently activated, functioning as a central adaptive transcriptional program. • Sustained NF-κB activity integrates tumor progression, immune evasion, metabolic rewiring, and resistance to radiotherapy, chemotherapy, and ferroptosis. • Targeting NF-κB-dependent adaptive modules offers a more precise therapeutic strategy than global NF-κB inhibition in hepatocellular carcinoma. Hepatocellular carcinoma (HCC) develops predominantly in the context of chronic liver inflammation and remains a leading cause of cancer-related mortality worldwide. Increasing evidence indicates that nuclear factor-κB (NF-κB) signaling plays a central role in linking inflammatory stress to malignant progression in HCC. Beyond transient inflammatory activation, NF-κB is pathologically stabilized through alterations in proteostasis, kinase signaling, and loss of endogenous inhibitory circuits, resulting in sustained transcriptional activity. This persistent NF-κB signaling orchestrates multiple adaptive programs that collectively drive tumor growth, metabolic reprogramming, immune evasion, and resistance to therapy. In particular, NF-κB integrates proliferative and survival signaling with glycolytic dependence, redox homeostasis, epithelial–mesenchymal transition, and immunosuppressive remodeling of the tumor microenvironment. Moreover, NF-κB functions as a shared survival hub under therapeutic stress, promoting resistance to radiotherapy, chemotherapy, and ferroptosis-inducing strategies. Importantly, emerging evidence highlights the role of non-coding RNAs and tumor suppressors as endogenous brakes that restrain NF-κB activity, whose disruption contributes to its pathological fixation in HCC. In this review, we synthesize recent mechanistic and translational advances that redefine NF-κB as a central adaptive program in hepatocellular carcinoma. We further discuss the clinical implications of NF-κB signaling for tumor stratification and therapeutic intervention, emphasizing that effective targeting of HCC may require selective disruption of NF-κB-dependent adaptive modules rather than global pathway inhibition.