ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicEffects of Lactic Acid and Lactylation on Epigenetic Modifications and Gene Expression in TumorView all 5 articles
A Lactylation-Ferroptosis Cross-Talk Gene Signature Predicts Hepatocellular Carcinoma Prognosis and Reveals STMN1/PRDX1 as Therapeutic Targets
Provisionally accepted
- 1The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- 2People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- 3Guangxi Medical University, Nanning, China
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Abstract Hepatocellular carcinoma (HCC) presents great difficulties for diagnosis and prognosis. Metabolic reprogramming and ferroptosis resistance play critical roles in HCC development and progression. In this study, we combined transcriptome data from TCGA-LIHC (TCGA-LIHC represents the Liver Hepatocellular Carcinoma project in The Cancer Genome Atlas) to screen out lactylation-ferroptosis-related genes, named lactylation-ferroptosis-related genes (LFRGs). Based on the LASSO-Cox regression and multivariate analysis, a 4-gene-prognostic signature (STMN1, PRDX1, TP53, G6PD) was constructed to stratify HCC patients into two risk subgroups with obvious survival differences (P < 0.001). Functional validation demonstrated that STMN1/PRDX1 knockdown in MHCC-97H/SNU-449 cells could simultaneously decrease the expression of LDHA (lactylation enzyme) and GPX4 (ferroptosis inhibitor), and further inhibited cell proliferation and migration (P < 0.01). The risk model was positively correlated with tumor stage and TMB, TP53 mutation, and immunosuppressive microenvironment. Drug sensitivity profile analysis suggested that high-risk patients may be sensitive to Dactolisib/Trametinib, while low-risk patients showed resistance to Axitinib/Ibrutinib. Mechanistically, STMN1/PRDX1 act as dual hubs in lactate metabolism (stabilizing LDHA) and ferroptosis resistance (modulating GPX4). We identified the first lactylation-ferroptosis cross-talk signature to predict HCC prognosis and identified STMN1/PRDX1 as potential targets for treating HCC by stratifying therapies.
Keywords: hepatocellular carcinoma (HCC), lactylation, ferroptosis, prognostic analysis, Early-stage Biomarkers
Received: 31 Jul 2025; Accepted: 17 Nov 2025.
Copyright: © 2025 Meng, Liang, Li, Huang, Huang, Wang and LI. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Rensheng Wang, 13807806008@163.com
XIAOLONG LI, xlongli@outlook.com
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