Abstract
Mitophagy is suggested to be involved in tumor initiation and development; however, mitophagy heterogeneity in hepatocellular carcinoma (HCC) and its association with immune status and prognosis remain unclear. Differentially expressed genes (DEGs) were identified using expression profiles acquired from The Cancer Genome Atlas (TCGA). Mitophagy-related subtypes were identified using the ConsensusClusterPlus software. The differences in prognosis, clinical characteristics, and immune status, including immune cell infiltration, immune function, immune-checkpoint gene expression, and response to immunotherapy, were compared between subtypes. A mitophagy-related gene signature was constructed by applying least absolute shrinkage and selection operator regression to the TCGA cohort. The International Cancer Genome Consortium cohort and the cohort from Peking Union Medical College Hospital were utilized for validation. Carbonyl cyanide m-chlorophenylhydrazone was used to induce mitophagy in HCC cell lines to obtain our own mitophagy signature. Real-time polymerase chain reaction was used for the experimental validation of the expression of model genes. Two mitophagy-related subtypes with distinct prognoses, clinical characteristics, immune states, and biological function patterns were identified based on the mitophagy-related DEGs. The subtype that showed higher mitophagy-related DEG expression had worse survival outcomes, suppressed immune function, higher immune-checkpoint gene expression, and a better response to immunotherapy, indicating that this subpopulation in HCC may benefit from immune-checkpoint blockade therapy and other immunotherapies. A risk model consisting of nine mitophagy-related genes was constructed and its performance was confirmed in two validation cohorts. The risk score was an independent risk factor even when age, sex, and tumor stage were considered. Our study identified two distinct mitophagy subtypes and built a mitophagy signature, uncovering mitophagy heterogeneity in HCC and its association with immune status and prognosis. These findings shed light on the treatment of HCC, especially with immunotherapy.