Cardiorespiratory fitness-associated gene signature for prognosis in hepatocellular Carcinoma: Computational prediction and in vivo validation

Cardiorespiratory fitness (CRF) plays a crucial role in cancer progression and prognosis, yet its molecular mechanisms remain poorly understood. This study aims to develop a prognostic model based on CRF-related genes in hepatocellular carcinoma (HCC). Using data from four cohorts, we identified 13 CRF-related genes and constructed a prognostic model through LASSO regression, selecting three key genes: CKAP4, LMNB1, and LEAP2. The model was validated across multiple datasets, including the TCGA and ICGC, demonstrating robust predictive accuracy for survival outcomes. High-risk patients identified by the model exhibited immune-suppressive microenvironments, lower CD8⁺ T-cell infiltration, and enrichment of pathways such as PI3K-AKT, p53, and Wnt signaling. Notably, exercise training improved CRF-related gene expression and increased CD8⁺ T-cell infiltration, emphasizing the therapeutic potential of physical activity. These findings underscore the utility of CRF-related genes as prognostic markers in HCC and highlight the interplay between CRF and tumor immunity, offering novel insights for personalized treatment strategies.