Dear Editor,
We are deeply grateful to Professors Aoki, Nishida, and Kudo for their thoughtful and insightful correspondence in response to our editorial [
1,
2]. It was a privilege to comment on their impactful study, which proposed a novel molecular classification of hepatocellular carcinoma (HCC) by integrating zonation-based metabolic features with oncogenic signaling pathways [
3]. This correspondence significantly enriched our understanding of the five molecular subtypes introduced by the authors. The references cited further strengthened the scientific and clinical relevance of this classification system in interpreting the heterogeneity of HCC. We believe these molecular phenotypes have strong potential as practical clinical tools for prognostication and treatment stratification in HCC. Furthermore, we hope to validate this classification framework in external international cohorts to assess its reproducibility across diverse populations, which would support its applicability in broader clinical contexts.
The authors’ discussion on metabolic reprogramming and immune heterogeneity in glycolysis-high HCCs was particularly insightful. As emphasized, increased glycolytic activity does not necessarily correlate with lactate accumulation, and this metabolic–immune discrepancy should be considered in interpreting the tumor microenvironment [
4]. The commentary on the IL-6/JAK/STAT3-high subtype was also valuable. As the authors rightly noted, defining this subtype as immune-active or inflamed may be premature. Given the context-dependent roles of IL-6/JAK/STAT3 signaling in both immunosuppression and antitumor immunity, further functional and clinical validation is essential to clarify its role in HCC [
5].
Once again, we thank the authors for this meaningful academic exchange and look forward to continued collaboration to advance precision classification and therapy for HCC.
FOOTNOTES
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Authors’ contribution
EJJ designed and wrote the manuscript; PSS supervised the whole project and wrote the manuscript.
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Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
REFERENCES
- 1. Aoki T, Nishida N, Kudo M. Correspondence to editorial on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway.”. Clin Mol Hepatol 2025 Apr 28;doi: 10.3350/cmh.2025.0435.
- 2. Jang EJ, Sung PS. A novel link between tumor cell metabolism and patient prognosis: Editorial on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway”. Clin Mol Hepatol 2025 Apr 16;doi: 10.3350/cmh.2025.0395.
- 3. Aoki T, Nishida N, Kurebayashi Y, Sakai K, Fujiwara N, Tsurusaki M, et al. Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway. Clin Mol Hepatol 2025;31:981-1002.
- 4. Chen J, Huang Z, Chen Y, Tian H, Chai P, Shen Y, et al. Lactate and lactylation in cancer. Signal Transduct Target Ther 2025;10:38.
- 5. Thuya WL, Cao Y, Ho PC, Wong AL, Wang L, Zhou J, et al. Insights into IL-6/JAK/STAT3 signaling in the tumor microenvironment: Implications for cancer therapy. Cytokine Growth Factor Rev 2025 Jan 17;doi: 10.1016/j.cytogfr.2025.01.003.
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