Machine learning analysis identified NNMT as a potential therapeutic target for hepatocellular carcinoma based on...

Programmed cell death (PCD) plays a critical role in cancer biology, influencing tumor progression and treatment response. This study aims to investigate the role of PCD-related genes in hepatocellular carcinoma (HCC), identifying potential prognostic biomarkers and therapeutic targets to enhance patient outcomes. Data from the GEO, TCGA, and ICGC databases were analyzed to identify differentially expressed genes associated with PCD in HCC. A cell death signature (CDS) model was constructed based on seven key PCD genes using machine learning techniques, including Random Survival Forest and Cox regression models. The model was validated across multiple cohorts to evaluate its predictive accuracy for clinical outcomes, immune infiltration, and therapeutic response, and further validation of the relationship between NNMT overexpression and clinical prognosis using tumor tissue microarray data, and in vitro experiments to confirm the impact of NNMT overexpression on cell proliferation and apoptosis. A total of 183 differentially expressed genes were identified, leading to the construction of a CDS model that incorporates seven key PCD-related genes (PRGs). The CDS showed significant associations with overall survival, immune cell infiltration, and therapeutic response in HCC patients. High CDS scores were linked to poorer prognosis, increased tumor immune exclusion, and decreased efficacy of immunotherapy and conventional treatments. The model demonstrated strong predictive performance across independent validation cohorts, underscoring its potential as a valuable prognostic tool. Additionally, NNMT overexpression promotes HepG2 proliferation, inhibits apoptosis, and correlates with poor prognosis in HCC patients. This study established a prognostic model for HCC based on PCD, and the CDS holds promise as a powerful tool for personalized risk assessment and treatment planning in HCC. Moreover, the model gene NNMT may serve as a potential therapeutic target for HCC.