Biochem Biophys Res Commun. 2026 Sep 30;838:154646. doi: 10.1016/j.bbrc.2026.154646. Online ahead of print.

ABSTRACT

Mitophagy, a selective form of autophagy, has been implicated in tumor progression and therapeutic resistance; however, its prognostic significance in hepatocellular carcinoma (HCC) remains unclear. In this study, we comprehensively evaluated the role of mitophagy-related genes in HCC using multi-omics data. Gene expression profiles were obtained from the TCGA-LIHC and GSE14520 cohorts, and mitophagy-related genes were retrieved from the GeneCards database. Twenty differentially expressed mitophagy-related genes with prognostic value (pDEMGs) were identified, and consensus clustering stratified HCC patients into two clusters with significantly different survival outcomes (P = 0.001). A mitophagy enrichment score (MIES) was then calculated using single-sample gene set enrichment analysis (ssGSEA). Elevated MIES was associated with poorer overall survival (HR = 2.17, P = 0.005), metabolic activation, immune suppression, and differential drug sensitivity. Single-cell analysis of the GSE140228 dataset revealed heterogeneous MIES activity across cell populations, with relatively higher enrichment observed in proliferating T cells and dendritic cells. A six-gene prognostic signature (ACTR6, GAPDH, ATIC, ANP32E, CCT6A, and BSG) was developed using LASSO-Cox regression, which effectively stratified patients into high- and low-risk groups with distinct overall survival outcomes (1-, 3-, and 5-year AUCs: 0.780, 0.682, and 0.690, respectively). The risk score was correlated with immune infiltration patterns, mutational landscape, and chemotherapy response. qPCR validation further confirmed the upregulation of ACTR6, CCT6A, ATIC, and BSG in HCC cells. Collectively, these findings establish a mitophagy-related scoring system that reflects immune and genomic characteristics, as well as a six-gene signature with independent prognostic value, highlighting the potential clinical relevance of mitophagy in HCC.

PMID:42828884 | DOI:10.1016/j.bbrc.2026.154646

Clin Mol Hepatol. 2026 Mar 11. doi: 10.3350/cmh.2025.1269. Online ahead of print.

ABSTRACT

BACKGROUND/AIMS: Lenvatinib resistance and immune exclusion limit outcomes in HCC. We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and PD-1 blockade.

METHODS: We established LS/LR HCC models and employed multi-omics (proteomics/RNA-seq), ChIP, luciferase, and RIP assays to map HKDC1 regulation. Tumor immunity was profiled by scRNA-seq, mIHC, and flow cytometry. SPD + lenvatinib efficacy was tested in cell lines, patient-derived organoids/xenografts. Tested therapy effect in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion; and analyzed a postoperative cohort (n = 40) treated with lenvatinib + PD-1.

RESULTS: HKDC1, upregulated in LR HCC, was transcriptionally activated by USF1 and promoted SMS-mediated polyamine rewiring. This impaired CD8⁺ T-cell metabolism, reversible by HKDC1 knockdown or spermidine (SPD). SPD synergized with lenvatinib, triggering autophagy and suppressing tumor growth in vitro and in vivo. High HKDC1 predicted poor response and survival in patients receiving lenvatinib + aPD-1.

CONCLUSIONS: A USF1/HKDC1/SMS axis couples polyamine metabolism to immune dysfunction and lenvatinib resistance. HKDC1 is a predictive biomarker and therapeutic node and support polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.

PMID:41812646 | DOI:10.3350/cmh.2025.1269