To establish a prognostic risk model for hepatocellular carcinoma (HCC) patients based on mitophagy-related genes (MRGs) from TCGA and ICGC databases, and to screen small molecule drugs with therapeutic potential.

RNA sequencing data and clinical information of HCC patients were downloaded from TCGA and ICGC databases. MRGs were retrieved and collected from Reactome signaling pathway database. Univariate Cox regression and Lasso regression analyses were employed to establish the prognostic risk model using TCGA cohort as the training data set and ICGC cohort as the verification set. The nomogram was plotted with R software "rms" package. The differential genes between the high-risk and low-risk groups in the prognostic risk model were selected with R software "limma" package. Small molecule drugs with therapeutic potential were screened out from the CMap database using the differential genes.

The expression levels of 19 MRGs were up-regulated, whereas that of PINK was down-regulated in the tumor tissues of TCGA and ICGC cohorts. All 12 MRGs were the risk factors for the clinical prognosis in two cohorts. A prognostic risk model of 5-MRGs markers was established by Lasso regression analysis, including casein kinase 2β polypeptide (CSNK2B), mitofusin 1 (MFN1), phosphoglycerate mutase family member 5 (PGAM5), translocase of outer mitochondrial membrane (TOMM) 5 and TOMM22 genes. Kaplan-Meier survival analysis demonstrated that prognosis in the high-risk groups in training and verification sets was poorer, and the median survival was shorter. ROC curve indicated this model yielded high predictive value for the prognosis of HCC patients. Multivariate Cox analysis demonstrated that mitophagy score was an independent factor affecting the prognosis of HCC patients (HR=2.68, 95%CI: 1.65-4.36, P<0.001). In the TCGA cohort, a nomogram was plotted combining tumor staging, grading, T staging and mitophagy score to predict the survival of HCC patients. 4 small molecular drugs with the potential to reverse the poor prognosis of patients in high-risk groups were screened out from the CMap database, including DL-thiorphan, blebbistatin, talampicillin and puromycin.

In this study, a stable prognostic risk model and nomogram are constructed based on MRGs, and small molecular drugs that might have therapeutic potential are screened out by differential genes in different risk groups.