Mol Med Rep. 2026 May;33(5):156. doi: 10.3892/mmr.2026.13866. Epub 2026 Apr 3.
ABSTRACT
Lung cancer is an aggressive malignancy associated with a rapid progression and poor prognosis, for which immunotherapy only exhibits modest efficacy in most patients. In lung cancer, high lactate is associated with a low immunotherapy response and shortened survival; however, causal lactylation‑related genes remain to be elucidated. In the present study, candidate genes were screened using Mendelian randomization (MR) analysis, with expression quantitative trait loci data and genome‑wide association study summary statistics used as analytical resources. A total of 46 lactylation‑related genes were included in the MR analysis, and multiple testing correction was performed using the false discovery rate (FDR) and Bonferroni methods to control the false‑positive risk. MR identified three core genes [platelet‑type phosphofructokinase; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; and stathmin 1 (STMN1)]. Among these genes, only STMN1 was significantly associated with increased lung cancer risk (inverse variance weighting original P=0.005, FDR‑corrected P=0.014995, Bonferroni‑corrected P=0.014995, odds ratio=1.741, 95% confidence interval: 1.182‑2.564), with robust results confirmed by heterogeneity/pleiotropy/sensitivity analyses. Subsequently, transcriptomic analysis was conducted to assess STMN1 expression in lung cancer tissues and its association with patient survival. In vitro (cell proliferation, migration, invasion and apoptosis assays) and in vivo experiments (murine tumor models) were also conducted to explore the function of STMN1. STMN1 exhibited upregulation in lung cancer tissues, and was associated with a shorter survival, reduced antitumor immune cell infiltration and an immunosuppressive tumor microenvironment (TME) phenotype. STMN1 knockdown inhibited lung cancer malignancy both in vitro and in vivo, and modulated key markers, whereas its overexpression exhibited the opposite effects. Additionally, STMN1 promoted global histone lactylation and histone H3 lysine 18 lactylation in lung cancer cells, establishing a direct functional link between STMN1 and the lactylation pathway. In conclusion, STMN1 is a lactylation‑related causal oncogene in lung cancer, driving progression via malignant phenotypes, and its high expression is associated with an immunosuppressive TME that may synergistically facilitate tumor progression. Therefore, STMN1 may be considered a novel target for lung cancer therapy.
PMID:41930463 | DOI:10.3892/mmr.2026.13866
