A lactylation-ferroptosis cross-talk gene signature predicts hepatocellular carcinoma prognosis and reveals STMN1/PRDX1 as therapeutic targets

作者：Jiali Meng, Chunyan Liang, Ling Li, Qiqi Huang, Weimei Huang, Rensheng Wang, Xiaolong Li · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1677089 · 被引用次数：3 · 研究领域：Ferroptosis and cancer prognosis、Clusterin in disease pathology、Cancer, Lipids, and Metabolism

Introduction: Hepatocellular carcinoma (HCC) presents great difficulties for diagnosis and prognosis. Metabolic reprogramming and ferroptosis resistance play critical roles in HCC development and progression. Methods: We combined transcriptome data from TCGA-LIHC to screen out lactylation-ferroptosis-related genes (LFRGs). Based on LASSO-Cox regression and multivariate analysis, a 4-gene-prognostic signature (STMN1, PRDX1, TP53, G6PD) was constructed. Results: The signature stratified 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 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). Discussion: 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.