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This is a In Vitro Study study.

November 10, 2025Frontiers in Immunology0 citationsOpen Access

A mitochondrial lipid metabolism–related gene signature predicts prognosis and immune landscape in colorectal cancer

Key Points

To evaluate the prognostic significance of mitochondrial lipid metabolism-related genes in colorectal cancer (CRC).
Systematic evaluation of gene expression profiles in CRC patients.
Constructed a risk model using TCGA and GEO databases.
Analyzed tumor microenvironment, immune cell infiltration, and drug sensitivity.
Identified key genes linked to mitochondrial lipid metabolism.
Developed a nomogram to predict patient outcomes based on risk score and clinical variables.
Findings indicate varied immune cell infiltration across risk groups, correlating with tumor microenvironment characteristics.

Abstract

Background Colorectal cancer (CRC) is a highly aggressive gastrointestinal malignancy with significant global health consequences. While mitochondrial lipid metabolism genes are known to influence CRC progression, their prognostic relevance remains inadequately explored. Methods This study systematically evaluated the expression profiles and prognostic significance of mitochondrial lipid metabolism-related genes in CRC patients. A risk model was constructed using data from the TCGA and GEO databases. Additionally, we examined the tumor microenvironment (TME), immune cell infiltration, tumor mutation burden, microsatellite instability (MSI), and drug sensitivity. Key genes associated with core mitochondrial lipid metabolism were identified and functionally validated through a series of in vitro cellular experiments. Results Mitochondrial lipid metabolism-associated genes were identified, including ABHD4, ABHD8, HDHD5, PNPLA4, GK5, CPT2, YJEFN3, CRYAB, HSPA1A, MAPK1, ATG7, HDAC3, and ACAT2. A nomogram integrating the risk score with key clinical variables (pTNM stage and age) was developed to predict patient outcomes. Significant variations in immune cell infiltration were observed between risk groups. Immune microenvironment analysis revealed significant differences in immune cell infiltration between risk groups, and the risk score was significantly correlated with the expression of TME-related genes and immune checkpoint molecules, indicating a markedly immunosuppressive microenvironment in the high-risk group. Additionally, TIDE analysis showed that combining the risk score with immune, stromal scores and MSI could more effectively predict the benefit of immunotherapy. Furthermore, in vitro experiments demonstrated that knockdown of two key genes, ABHD4 and YJEFN3, significantly suppressed CRC cell proliferation, migration, and invasion, supporting their potential oncogenic roles. Conclusions This mitochondrial lipid metabolism-based risk model represents a promising prognostic biomarker, offering potential guidance for personalized therapeutic strategies in CRC management.

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