Coiled-coil-helix-coiled-coil-helix Domain Containing 1 Promotes Hepatocellular Carcinoma Progression by Regulating Transforming Growth Factor Beta Receptor 1 in the Tumor Immune Microenvironment

<b><i>Background:</i></b> Coiled-coil-helix-coiled-coil-helix domain containing 1 (CHCHD1) is a mitochondrial protein involved in oxidative phosphorylation and mitochondrial protein synthesis. While its functions have been explored in basic mitochondrial biology, the role of this process in hepatocellular carcinoma (HCC) remains poorly understood. <b><i>Materials and Methods:</i></b> We performed transcriptomic analysis on 272 HCC and 50 normal liver tissue samples to assess CHCHD1 expression. Correlations with clinical features were analyzed using Pearson coefficients. Prognostic relevance was evaluated using receiver operating characteristic analysis. Functional studies in SMMC-7721 cells included transwell migration/invasion assays, as well as western blotting, to assess epithelial-mesenchymal transition (EMT) markers and transforming growth factor (TGF)-β1 signaling. Gene set enrichment analysis (GSEA), single-cell RNA sequencing (scRNA-seq), and immune infiltration analyses were conducted to investigate immunoregulatory functions. <b><i>Results:</i></b> CHCHD1 expression was significantly upregulated in HCC tissues (1.38-fold, <i>p</i> < 0.001) and correlated positively with tumor size (<i>R</i> = 0.45), vascular invasion (<i>R</i> = 0.56), and advanced Barcelona Clinic Liver Cancer stage (<i>R</i> = 0.62; all <i>p</i> < 0.001). High CHCHD1 predicted shorter progression-free survival (area under the curve = 0.938; 95% confidence interval 0.910-0.965; <i>p</i> = 0.039). Overexpression of CHCHD1 enhanced cell migration and invasion, promoted EMT (downregulation of E-cadherin and upregulation of vimentin), and activated TGF-β1 signaling. GSEA linked CHCHD1 to immune-related pathways. scRNA-seq localized CHCHD1 to myeloid-derived suppressor cells, showing potential interactions with TGF-β receptor 1. CHCHD1 expression correlated with Th2 cell infiltration (<i>R</i> = 0.57, <i>p</i> = 0.025) and programmed cell death 1 expression (<i>p</i> = 0.027). <b><i>Conclusion:</i></b> CHCHD1 promotes EMT and immune evasion in HCC via TGF-β1 signaling, implicating it as a promising biomarker and therapeutic target.