Lactic acid promotes non-small cell lung cancer progression by down-regulating hexokinase 1 via histone lactylation: A Mendelian randomization study

The aim of this study was to investigate the effect of lactic acid down-regulation of hexokinase 1 (HK1) on non-small cell lung cancer (NSCLC) through histone lactylation by Mendelian randomization (MR). Genes related to HK1 and NSCLC targets were analyzed using genome-wide association study summary statistics downloaded from public databases. Single-nucleotide polymorphisms associated with HK1 were selected as instrumental variables, and MR analyses were performed using inverse-variance weighted as the primary study method, and MR-Egger, weighted median, simple mode, and weighted mode as complementary methods in order to assess whether HK1 is a protective factor for NSCLC, and to provide further evidence that lactic acid is a risk factor for NSCLC. The results showed that HK1 was significantly and negatively associated with the risk of NSCLC using an inverse-variance weighted method (odds ratio = 0.93, 95% confidence interval = 0.89-0.98, P < .05). This suggests that for every 1-unit increase in genetically predicted HK1 expression, the odds of developing NSCLC decrease by approximately 7%. No significant heterogeneity or directional pleiotropy was detected (MR-Egger intercept P > .05). Leave-one-out sensitivity analysis confirmed the robustness of the findings. This MR study provides genetic evidence that lactic acid may down-regulate HK1 expression via histone lactylation, thereby increasing the risk of NSCLC. However, limitations include the restriction to European ancestry, limited number of instrumental single-nucleotide polymorphisms due to stringent thresholds, and potential residual pleiotropy not captured by current methods. These factors may affect the generalizability and causal interpretability of the findings.