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

[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.