Hong Lin

Hepatocellular carcinoma (HCC) is highly heterogeneous with unpredictable outcomes. Mitochondrial dysfunction drives HCC progression, but its prognostic implications remain unclear. This study aimed to develop a mitochondrial-related prognostic model for HCC. We analyzed transcriptomic data from 370 HCC patients from The Cancer Genome Atlas (TCGA) using consensus clustering of mitochondrial pathway genes. A mitochondrial-associated scoring model (MASM) was developed via least absolute shrinkage and selection operator (LASSO) and Cox regression, validated across independent cohorts [GSE116174 and the International Cancer Genome Consortium Liver Cancer-RIKEN, Japan (ICGC-LIRI)]. Functional roles of MRPS15, a key gene in the model, were investigated through in vitro experiments and subcutaneous tumor formation experiment in nude mice. Consensus clustering identified three mitochondrial subtypes with distinct metabolic profiles: subtype A exhibited elevated oxidative phosphorylation (OXPHOS) and preserved metabolic homeostasis; subtype B showed adaptive metabolic reprogramming; subtype C displayed selective activation of biosynthetic pathways despite widespread mitochondrial dysfunction. The MASM prognostic signature, comprising eight mitochondrial genes, achieved predictive accuracy with area under the curve (AUC) values of 0.805, 0.751, and 0.742 for 1-, 3-, and 5-year survival, respectively, and showed favorable trends compared with clinical staging. MRPS15 was validated as a critical regulator of HCC cell proliferation, invasion, migration, and apoptosis, primarily through sustaining OXPHOS and redox homeostasis. This study establishes a mitochondrial-based classification and eight-gene MASM model for HCC, which stratifies patients into three subtypes with distinct metabolic, genomic, and immune profiles. The model outperforms traditional staging in survival prediction. MRPS15 is validated as a key oncogenic driver sustaining OXPHOS. These findings provide a framework for personalized therapy and warrant prospective clinical validation.

Background: Breast cancer (BC) represents a highly heterogeneous malignancy and continues to be a leading source of death among women worldwide. Enhancing diagnostic and therapeutic approaches necessitates a thorough grasp of the underlying molecular pathways and the identification of dependable biomarkers. Although palmitoyl transferases, particularly ZDHHC9, have been associated with the progression of various cancers, their specific role in BC remains incompletely understood.Methods: In this investigation, TCGA and GTEx databases were utilized to analyze the expression patterns of ZDHHC9 and to evaluate its prognostic significance. Moreover, the regulatory pathways involving ZDHHC9 were explored via co-expression analysis and differential gene enrichment studies. Insights into ZDHHC9 expression across different cell types and its potential oncogenic pathways were derived from scRNA sequencing analysis. Additionally, immunophenoscore (IPS), EaSIeR and immunotherapy cohorts were utilized to predict immunotherapy responses. The biological significance of ZDHHC9 was verified through in vitro and in vivo experiments.Results: Our findings revealed that ZDHHC9 is markedly overexpressed in BC, with elevated levels of ZDHHC9 being correlated with poor survival outcomes, suggesting its role as an independent risk factor in BC. Furthermore, high ZDHHC9 expression was found to be associated with multiple immune cell types within BC. Notably, patients exhibiting lower ZDHHC9 expression demonstrated a higher likelihood of benefitting from immunotherapy. Lastly, the vivo and vitro experiments consistently demonstrated that suppression of ZDHHC9 expression could reduce BC cell proliferation.Conclusions: This study highlights ZDHHC9 as a potential prognostic marker, a regulator of tumor immunity, and a biomarker of therapeutic response in BC, offering a promising avenue for improving BC diagnosis and treatment.