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

Nat Med. 2026 Oct 2. doi: 10.1038/s41591-026-04673-3. Online ahead of print.

ABSTRACT

Urine biomarkers promise to improve noninvasive detection and molecular characterization of genitourinary malignancies. Here we describe urine random priming and affinity capture of cell-free RNA (cfRNA) fragments for enrichment analysis by sequencing (uRARE-seq), a liquid biopsy method for urine cfRNA profiling, and apply it to 683 urine samples from patients with cancer and controls. Urine cfRNA contained transcripts from genitourinary tissues and, in patients with prostate, kidney or bladder cancer, tumor-derived transcripts. uRARE-seq demonstrated 95% sensitivity at 90% specificity for detecting localized bladder cancer. The method outperformed urine tumor DNA analysis and was unaffected by the presence of field-effect mutations. Urine cfRNA analysis also sensitively detected minimal residual disease and distinguished complete molecular responses after surgery from those after intravesical Bacillus Calmette-Guérin (BCG). Pretreatment urine from complete responders to BCG was enriched for T cell and other immune signatures, suggesting a preexisting antitumor immune response, whereas nonresponders showed higher expression of proliferation-related genes. In pretreatment urine from 114 patients, this biological difference enabled development of a biomarker predicting likelihood of response to BCG versus chemotherapy (area under the curve 0.93) that was strongly associated with risk of recurrence. Urine cfRNA analysis is therefore a promising biomarker approach for bladder cancer and potentially other urologic malignancies, although prospective studies are needed to assess its clinical utility.

PMID:42827132 | DOI:10.1038/s41591-026-04673-3