NLR Risk Score for Predicting Patient Prognosis in Hepatocellular Carcinoma and Identification of Oncogenic Role of NLRP5 in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths. The Nod-like receptor (NLR) family is involved in innate immunity and tumor progression, but its role in HCC remains unclear. This study aimed to evaluate the prognostic value and biological function of NLR genes in HCC.

Transcriptomic and clinical data from The Cancer Genome Atlas were analyzed using nonnegative matrix factorization (NMF) to classify HCC into molecular subtypes. Differentially expressed genes were used to build an NLR-based prognostic model (NLR_score) through univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression. Predictive performance and correlation with chemotherapy sensitivity were assessed. NLR family pyrin domain containing 5 (NLRP5) was identified as a key oncogene and validated via in vitro assays, including cell counting kit-8 (CCK-8), colony formation, transwell, and flow cytometry in vivo xenograft models.

The two NMF-defined subtypes showed distinct survival outcomes. The NLR_score reliably predicted prognosis and was associated with sensitivity to six chemotherapeutic drugs. NLRP5 knockdown suppressed HCC cell proliferation, migration, and invasion in vitro and reduced tumor growth in vivo. Mechanistically, NLRP5 modulated the p53 signaling pathway, influencing cell cycle and apoptosis.

This study developed an NLR-based prognostic model that effectively stratifies HCC patients by survival risk. NLRP5 was identified as a novel oncogene promoting HCC progression via the p53 pathway, suggesting its potential as a therapeutic target.