Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide, with a high mortality rate that is closely associated with chronic inflammation and aberrantly activated signaling pathways in the tumor microenvironment. As a central regulator of inflammatory responses, the IκB kinase (IKK)/nuclear factor-κB (NF-κB) signaling pathway plays a critical role in the proliferation, invasion, and immune escape of HCC. This study analyzes the clinical significance of the IKK/NF-κB pathway in predicting the prognosis of HCC patients.

Methods: A total of 206 HCC patients from 2022 to 2025 were included in this study and divided into the death group (n = 117) and the survival group (n = 89) according to their survival status. The content of IKK, NF-κB p65 and downstream proteins interleukin-6 (IL-6) and cyclin D1 were analyzed using enzyme-linked immunosorbent assay (ELISA). Combined with the clinicopathological characteristics, Kaplan–Meier survival analysis and Cox proportional hazards model were used to evaluate the association between pathway activity and the risk of patient death.

Results: There was no significant difference in the baseline data between the two groups of patients (p > 0.05). The serum content of IKK and NF-κB p65 in the death group was significantly higher than that in the survival group (p < 0.05). Survival analysis showed that the high expression of IKK and NF-κB p65 was significantly associated with reduced overall survival (OS) in patients (p < 0.05). Multivariate Cox regression showed that IKK, NF-κB p65 and IL-6 were independent predictors of poor prognosis (p < 0.05).

Conclusion: Aberrant activation of the IKK/NF-κB signaling pathway is associated with death risk in HCC patients, serving as an independent prognostic marker.