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Background <p>Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC), but response is highly variable. The systemic metabolic impact of TACE and its connection to tumor-intrinsic factors governing efficacy remain poorly understood. We hypothesized that by comparing host fecal metabolomics with tumor transcriptomics, we could identify convergent pathways suggestive of a gut-liver axis signature of TACE response.</p> Methods <p>We performed untargeted fecal metabolomics in a prospective paired cohort of 30 HCC patients sampled before TACE and again on post-TACE day 4, an early time point selected to capture acute ischemic, inflammatory, and metabolic perturbations after embolization. To characterize tumor-intrinsic programs associated with efficacy, we analyzed the independent public transcriptomic dataset GSE104580 containing pre-treatment tumors from TACE responders and non-responders. Cross-cohort integration was conducted at the pathway level to identify convergent biological themes. For metabolomics, paired univariate testing with Benjamini–Hochberg false discovery rate (FDR) correction and Variable Importance in Projection (VIP) &gt; 1 from PLS-DA were used; for transcriptomics, differential expression used adjusted p &lt; 0.05 and |log2FC|&gt; 1, followed by GSEA.</p> Results <p>TACE induced a shift in the fecal metabolome, with significant enrichment of glycerophospholipid metabolism, together with changes in bile acid-related metabolites and tryptophan/vitamin B6-related metabolites. Lysophosphatidylcholines (LysoPCs), including LysoPC (22:4), and bile acid-related metabolites were increased after TACE, consistent with acute treatment-associated tissue metabolic perturbation. Independent transcriptomic analysis revealed that responder tumors were enriched for primary bile acid biosynthesis, fatty acid degradation, and tryptophan metabolism, with higher expression of CYP7A1, ACOX1, IDO1, and TDO2, whereas non-responders were enriched for Cell cycle, DNA replication, and ribosome-related programs. Because the metabolomics and transcriptomics datasets were derived from separate cohorts, these convergent findings support a pathway-level cross-cohort model rather than direct patient-level tumor-fecal linkage.</p> Conclusion <p>Our comparative analysis suggests a potential gut-liver axis signature associated with TACE efficacy. We therefore present fecal LysoPC as a candidate non-invasive pharmacodynamic readout of acute post-TACE tissue injury and host-microenvironmental perturbation rather than a tumor-necrosis-specific biomarker. Likewise, the convergence on bile acid and tryptophan metabolism suggests that a responder-associated tumor metabolic phenotype may be relevant to TACE sensitivity. These findings offer potential non-invasive biomarkers and highlight new therapeutic targets to enhance TACE efficacy.</p>

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Integrative multi-omics analysis reveals a gut-liver axis signature of metabolic reprogramming associated with response to transarterial chemoembolization in hepatocellular carcinoma

  • 期刊论文

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  • 发表日期：

    2026年6月17日

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  • Xiaojing Ren,
  • Zhenyu Liu,
  • Yifan Wang,
  • Peng Guo,
  • Shuyao Cheng,
  • Ruiping Zhang

摘要

Background

Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC), but response is highly variable. The systemic metabolic impact of TACE and its connection to tumor-intrinsic factors governing efficacy remain poorly understood. We hypothesized that by comparing host fecal metabolomics with tumor transcriptomics, we could identify convergent pathways suggestive of a gut-liver axis signature of TACE response.

Methods

We performed untargeted fecal metabolomics in a prospective paired cohort of 30 HCC patients sampled before TACE and again on post-TACE day 4, an early time point selected to capture acute ischemic, inflammatory, and metabolic perturbations after embolization. To characterize tumor-intrinsic programs associated with efficacy, we analyzed the independent public transcriptomic dataset GSE104580 containing pre-treatment tumors from TACE responders and non-responders. Cross-cohort integration was conducted at the pathway level to identify convergent biological themes. For metabolomics, paired univariate testing with Benjamini–Hochberg false discovery rate (FDR) correction and Variable Importance in Projection (VIP) > 1 from PLS-DA were used; for transcriptomics, differential expression used adjusted p < 0.05 and |log2FC|> 1, followed by GSEA.

Results

TACE induced a shift in the fecal metabolome, with significant enrichment of glycerophospholipid metabolism, together with changes in bile acid-related metabolites and tryptophan/vitamin B6-related metabolites. Lysophosphatidylcholines (LysoPCs), including LysoPC (22:4), and bile acid-related metabolites were increased after TACE, consistent with acute treatment-associated tissue metabolic perturbation. Independent transcriptomic analysis revealed that responder tumors were enriched for primary bile acid biosynthesis, fatty acid degradation, and tryptophan metabolism, with higher expression of CYP7A1, ACOX1, IDO1, and TDO2, whereas non-responders were enriched for Cell cycle, DNA replication, and ribosome-related programs. Because the metabolomics and transcriptomics datasets were derived from separate cohorts, these convergent findings support a pathway-level cross-cohort model rather than direct patient-level tumor-fecal linkage.

Conclusion

Our comparative analysis suggests a potential gut-liver axis signature associated with TACE efficacy. We therefore present fecal LysoPC as a candidate non-invasive pharmacodynamic readout of acute post-TACE tissue injury and host-microenvironmental perturbation rather than a tumor-necrosis-specific biomarker. Likewise, the convergence on bile acid and tryptophan metabolism suggests that a responder-associated tumor metabolic phenotype may be relevant to TACE sensitivity. These findings offer potential non-invasive biomarkers and highlight new therapeutic targets to enhance TACE efficacy.