Biochim Biophys Acta Mol Basis Dis. 2027 Jan;1873(1):168471. doi: 10.1016/j.bbadis.2026.168471. Epub 2026 Sep 24.

ABSTRACT

BACKGROUND: The global burden of metabolic-associated hepatocellular carcinoma (HCC) is increasing, with obesity emerging as a key causal factor. However, the molecular mechanisms linking lipid metabolic dysregulation to HCC progression and therapeutic vulnerability remain unclear.

METHODS: We analyzed Global Burden of Disease 2021 data to assess liver cancer burden attributable to metabolic risks from 1990 to 2021. Mendelian randomization was used to evaluate causal associations between metabolic traits and liver cancer risk. TCGA, GTEx, and GEO datasets were integrated to identify lipid stress-responsive regulators. Clinical relevance was assessed using public datasets and tissue microarray immunohistochemistry. Functional validation was performed in HCC cells and a high-fat diet-fed syngeneic mouse tumor model.

RESULTS: Liver cancer deaths and DALYs attributable to metabolic risks increased markedly from 1990 to 2021. Mendelian randomization showed that obesity-related traits, including BMI, waist circumference, and body fat percentage, were causally associated with liver cancer risk, whereas glycemic traits were not. Bioinformatics screening identified GPAT3 as a lipid metabolism regulator upregulated in HCC, induced by palmitic acid, associated with poor prognosis, and enriched in patients with higher BMI. Tissue microarray analysis confirmed increased GPAT3 protein expression in HCC and its association with higher BMI and GPX4 expression. GPAT3 depletion sensitized HCC cells to palmitic acid-induced ferroptosis, whereas Fer-1 rescue and GPAT3 overexpression supported its protective role. In vivo, FSG67 enhanced sorafenib-associated antitumor effects and increased tumor lipid peroxidation.

CONCLUSIONS: GPAT3 protects HCC cells from lipid stress-induced ferroptosis and represents a potential metabolic vulnerability in obesity-associated HCC.

PMID:42785105 | DOI:10.1016/j.bbadis.2026.168471

Biochim Biophys Acta Mol Basis Dis. 2027 Jan;1873(1):168471. doi: 10.1016/j.bbadis.2026.168471. Epub 2026 Sep 24.

ABSTRACT

BACKGROUND: The global burden of metabolic-associated hepatocellular carcinoma (HCC) is increasing, with obesity emerging as a key causal factor. However, the molecular mechanisms linking lipid metabolic dysregulation to HCC progression and therapeutic vulnerability remain unclear.

METHODS: We analyzed Global Burden of Disease 2021 data to assess liver cancer burden attributable to metabolic risks from 1990 to 2021. Mendelian randomization was used to evaluate causal associations between metabolic traits and liver cancer risk. TCGA, GTEx, and GEO datasets were integrated to identify lipid stress-responsive regulators. Clinical relevance was assessed using public datasets and tissue microarray immunohistochemistry. Functional validation was performed in HCC cells and a high-fat diet-fed syngeneic mouse tumor model.

RESULTS: Liver cancer deaths and DALYs attributable to metabolic risks increased markedly from 1990 to 2021. Mendelian randomization showed that obesity-related traits, including BMI, waist circumference, and body fat percentage, were causally associated with liver cancer risk, whereas glycemic traits were not. Bioinformatics screening identified GPAT3 as a lipid metabolism regulator upregulated in HCC, induced by palmitic acid, associated with poor prognosis, and enriched in patients with higher BMI. Tissue microarray analysis confirmed increased GPAT3 protein expression in HCC and its association with higher BMI and GPX4 expression. GPAT3 depletion sensitized HCC cells to palmitic acid-induced ferroptosis, whereas Fer-1 rescue and GPAT3 overexpression supported its protective role. In vivo, FSG67 enhanced sorafenib-associated antitumor effects and increased tumor lipid peroxidation.

CONCLUSIONS: GPAT3 protects HCC cells from lipid stress-induced ferroptosis and represents a potential metabolic vulnerability in obesity-associated HCC.

PMID:42785105 | DOI:10.1016/j.bbadis.2026.168471

J Thorac Dis. 2026 Apr 30;18(4):353. doi: 10.21037/jtd-2025-1-2610. Epub 2026 Mar 20.

ABSTRACT

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by rapid progression, early metastasis, and high mortality, with limited effective long-term treatment options. B4GALT1, a β-1,4-galactosyltransferase, has been implicated in the malignant progression of various cancers, but its specific role and underlying mechanisms in SCLC remain largely unexplored. We conducted a multi-omics analysis and clinical sample study to explore the function of B4GALT1 in SCLC.

METHODS: This study comprehensively investigated the expression pattern, functional significance, and clinical relevance of B4GALT1 in SCLC. We conducted multi-omics analyses, including single-cell data processing, InferCNV analysis, and immune infiltration analysis, to explore the association between B4GALT1 and the immune microenvironment of SCLC and patient survival. To determine B4GALT1 as a potential circulating biomarker, quantitative data-independent acquisition (DIA) proteomics analysis was performed on serum samples from SCLC patients and healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to further verify the differential expression of serum B4GALT1 in a larger cohort of SCLC patients, to evaluate its diagnostic, prognostic, and treatment response predictive value.

RESULTS: Multi-omics analysis revealed that B4GALT1 expression was significantly associated with patient survival. The expression of B4GALT1 positively correlated with macrophage infiltration in the tumor and negatively correlated with CD4⁺ T cells in the tumor. There was a negative correlation in inactivated naïve B cells, eosinophils, and CD4 naïve T cells, while it showed a positive correlation in dendritic cells, M0/M1/M2 macrophages, natural killer (NK) cells, CD8 T cells, follicular helper T cells, and regulatory T cells. ELISA results showed that serum protein B4GALT1 expression was higher in patients with SCLC than in healthy controls. Elevated serum B4GALT1 protein levels correlated with poor treatment outcomes in patients with SCLC undergoing chemoradiotherapy.

CONCLUSIONS: Our findings establish B4GALT1 as a critical prognostic, diagnostic, and predictive biomarker in SCLC, with its expression closely linked to the tumor immune microenvironment and treatment response. Targeting B4GALT1 or its related pathways may represent a novel therapeutic strategy, and serum B4GALT1 holds promise as a liquid biopsy marker for SCLC patient stratification, monitoring, and guiding treatment decisions.

PMID:42182735 | PMC:PMC13190155 | DOI:10.21037/jtd-2025-1-2610

J Thorac Dis. 2026 Apr 30;18(4):353. doi: 10.21037/jtd-2025-1-2610. Epub 2026 Mar 20.

ABSTRACT

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by rapid progression, early metastasis, and high mortality, with limited effective long-term treatment options. B4GALT1, a β-1,4-galactosyltransferase, has been implicated in the malignant progression of various cancers, but its specific role and underlying mechanisms in SCLC remain largely unexplored. We conducted a multi-omics analysis and clinical sample study to explore the function of B4GALT1 in SCLC.

METHODS: This study comprehensively investigated the expression pattern, functional significance, and clinical relevance of B4GALT1 in SCLC. We conducted multi-omics analyses, including single-cell data processing, InferCNV analysis, and immune infiltration analysis, to explore the association between B4GALT1 and the immune microenvironment of SCLC and patient survival. To determine B4GALT1 as a potential circulating biomarker, quantitative data-independent acquisition (DIA) proteomics analysis was performed on serum samples from SCLC patients and healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to further verify the differential expression of serum B4GALT1 in a larger cohort of SCLC patients, to evaluate its diagnostic, prognostic, and treatment response predictive value.

RESULTS: Multi-omics analysis revealed that B4GALT1 expression was significantly associated with patient survival. The expression of B4GALT1 positively correlated with macrophage infiltration in the tumor and negatively correlated with CD4⁺ T cells in the tumor. There was a negative correlation in inactivated naïve B cells, eosinophils, and CD4 naïve T cells, while it showed a positive correlation in dendritic cells, M0/M1/M2 macrophages, natural killer (NK) cells, CD8 T cells, follicular helper T cells, and regulatory T cells. ELISA results showed that serum protein B4GALT1 expression was higher in patients with SCLC than in healthy controls. Elevated serum B4GALT1 protein levels correlated with poor treatment outcomes in patients with SCLC undergoing chemoradiotherapy.

CONCLUSIONS: Our findings establish B4GALT1 as a critical prognostic, diagnostic, and predictive biomarker in SCLC, with its expression closely linked to the tumor immune microenvironment and treatment response. Targeting B4GALT1 or its related pathways may represent a novel therapeutic strategy, and serum B4GALT1 holds promise as a liquid biopsy marker for SCLC patient stratification, monitoring, and guiding treatment decisions.

PMID:42182735 | PMC:PMC13190155 | DOI:10.21037/jtd-2025-1-2610