Abstract

Simple SummaryHepatocellular carcinoma (HCC) lacks reliable biomarkers for prognosis and actionable targets for therapies, prompting the need to identify molecules that can improve risk stratification and guide treatment decisions. We found two genes related to the mitochondria, LPCAT1 and MRPL9, developed and validated a model for prognosis, and demonstrated that both genes promote HCC progression by controlling AKT phosphorylation and cell-cycle checkpoints. These findings provide an applicable tool for prognosis and highlight LPCAT1 and MRPL9 as potential targets for therapies. We offered new avenues for improving patient management and individualized therapy in HCC.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 inhib