LPCAT1 and MRPL9 Promote Hepatocellular Carcinoma Progression via AKT Phosphorylation and Define a Mitochondrial...

Background/Objectives: Mitochondrial dysfunction plays a critical role in hepatocellular carcinoma (HCC) progression. This study aimed to identify mitochondrial-related prognostic genes and elucidate their functional mechanisms in HCC. Methods: Mitochondrial-related prognostic genes were screened from the TCGA and ICGC-LIHC cohorts. A prognostic risk model was constructed and validated in three external cohorts. Immunotherapy sensitivity between high- and low-risk groups was assessed using somatic mutation and immune infiltration analyses. Underlying molecular mechanisms were further validated through in vitro experiments in HCC cell lines. Results: Transcriptome analysis identified 15 mitochondrial-related prognostic genes, from which 10 candidates were refined using LASSO regression. Among them, LPCAT1 and MRPL9 were significantly associated with overall survival. The 2-MRG model (comprising LPCAT1 and MRPL9) demonstrated superior prognostic accuracy and better survival stratification across both internal and external cohorts. Functional enrichment analysis revealed significant metabolic dysfunction in the high-risk group. The high-risk group also exhibited a significantly higher tumor mutation burden and an enhanced predicted responsiveness to immunotherapy. In vitro, knockdown of MRPL9 or LPCAT1 inhibited the proliferation and migration of HCC cells by inducing G1/S arrest and G2/M arrest, respectively. Moreover, they also suppressed the AKT phosphorylation. Conclusions: We developed a robust 2-MRG prognostic model based on LPCAT1 and MRPL9 that effectively predicts HCC outcomes and supports individualized therapeutic decision-making. Both genes promote HCC progression by modulating the AKT phosphorylation and cell-cycle checkpoints, highlighting their potential as therapeutic targets.