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Background <p>Glycolytic markers such as carbonic anhydrase 9 (CA9) have been implicated in hepatocellular carcinoma (HCC) prognosis; however, sex-based differences and the underlying pathological mechanisms remain unclear. Herein, we investigated sex-stratified prognostic significance of CA9 and developed a pathomics-based predictive model.</p> Methods <p>Data from the TCGA-LIHC cohort were analyzed, to determine the optimal CA9 expression cutoff using the “survminer” package. Kaplan_Meier survival analysis and Cox regression were performed to assess sex-specific prognostic associations. Tissue segmentation was conducted using the Otsu method, and features extracted with PyRadiomics were optimized through a combined minimum redundancy maximum relevance_recursive feature elimination_Akaike Information Criterion pipeline to construct a logistic classifier. Ferroptosis-related pathways were interrogated using FerrDb V2 genes with gene set variation analysis (GSVA) and weighted gene co-expression network analysis (WGCNA). Model performance was evaluated using ROC-AUC and calibration curves.</p> Results <p>Patients with high CA9 expression experienced significantly shorter overall survival than those with low expression (42.37 vs. 84.4 months, <i>P</i> &lt; 0.001). CA9 emerged as an independent risk factor (HR = 2.131, <i>P</i> &lt; 0.001) with a more pronounced prognostic impact in males than in females (HR = 2.836 vs. 1.261, <i>P</i> = 0.038). The pathomics model achieved AUCs of 0.746 in the training cohort and 0.706 in the validation cohort; the predictive score (PS) strongly correlated with CA9 expression (<i>P</i> &lt; 0.001). Patients in the high-PS group had reduced survival (56.17 months vs. 82.87 months; <i>P</i> &lt; 0.001), with no significant sex-based difference observed (<i>P</i> = 0.17). Tumors with high PS exhibited TGF-β/mTOR signaling, whereas low-PS tumors demonstrated upregulated ferroptosis-related CGAS expression and enrichment of NADPH oxidase- and EGFR resistance-related pathways (<i>P</i> &lt; 0.01).</p> Conclusion <p>CA9 represents a sex-dimorphic prognostic biomarker in HCC. When combined with a pathomics model, it offers a precise framework for risk stratification and provides insight into the contribution of the glycolysis-ferroptosis axis to HCC progression.</p>

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Pathomic study on the correlation between carbonic anhydrase 9 expression and prognosis in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月6日

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  • Yuan Liu,
  • Caiwang Gao,
  • Riga Su,
  • Qiqige Badema,
  • Yiling Hu,
  • Xiehua Zhang

摘要

Background

Glycolytic markers such as carbonic anhydrase 9 (CA9) have been implicated in hepatocellular carcinoma (HCC) prognosis; however, sex-based differences and the underlying pathological mechanisms remain unclear. Herein, we investigated sex-stratified prognostic significance of CA9 and developed a pathomics-based predictive model.

Methods

Data from the TCGA-LIHC cohort were analyzed, to determine the optimal CA9 expression cutoff using the “survminer” package. Kaplan_Meier survival analysis and Cox regression were performed to assess sex-specific prognostic associations. Tissue segmentation was conducted using the Otsu method, and features extracted with PyRadiomics were optimized through a combined minimum redundancy maximum relevance_recursive feature elimination_Akaike Information Criterion pipeline to construct a logistic classifier. Ferroptosis-related pathways were interrogated using FerrDb V2 genes with gene set variation analysis (GSVA) and weighted gene co-expression network analysis (WGCNA). Model performance was evaluated using ROC-AUC and calibration curves.

Results

Patients with high CA9 expression experienced significantly shorter overall survival than those with low expression (42.37 vs. 84.4 months, P < 0.001). CA9 emerged as an independent risk factor (HR = 2.131, P < 0.001) with a more pronounced prognostic impact in males than in females (HR = 2.836 vs. 1.261, P = 0.038). The pathomics model achieved AUCs of 0.746 in the training cohort and 0.706 in the validation cohort; the predictive score (PS) strongly correlated with CA9 expression (P < 0.001). Patients in the high-PS group had reduced survival (56.17 months vs. 82.87 months; P < 0.001), with no significant sex-based difference observed (P = 0.17). Tumors with high PS exhibited TGF-β/mTOR signaling, whereas low-PS tumors demonstrated upregulated ferroptosis-related CGAS expression and enrichment of NADPH oxidase- and EGFR resistance-related pathways (P < 0.01).

Conclusion

CA9 represents a sex-dimorphic prognostic biomarker in HCC. When combined with a pathomics model, it offers a precise framework for risk stratification and provides insight into the contribution of the glycolysis-ferroptosis axis to HCC progression.