DNMT1 is associated with QDPR downregulation and chemotherapy response in lung adenocarcinoma

In lung adenocarcinoma (LUAD), DNA methylation-mediated gene silencing may contribute to tumor initiation, progression, and heterogeneity in treatment response. However, the key methyltransferases involved and their therapeutic potential have not been systematically characterized. This study aimed to address three major questions: which methylation-associated gene silencing events occur in LUAD, which upstream methyltransferase predominantly drives these events, and whether targeted inhibition of this enzyme can mitigate drug-resistant phenotypes and enhance chemosensitivity. Differential expression analysis was initially performed using the GSE75037 dataset to screen candidate genes. Expression quantitative trait locus (eQTL) and protein quantitative trait locus (pQTL) data were then integrated, and key candidate genes were prioritized according to the concordance in the directions of genetic effects. Subsequently, mediation Mendelian randomization analysis was conducted to determine whether the effect of locus-specific methylation on LUAD was mediated by QDPR expression, thereby providing genetic causal evidence that methylation contributes to transcriptional repression. In addition, the associations between DNA methylation-related enzymes and QDPR expression were analyzed in the GSE33532, GSE43458, and GSE75037 datasets, followed by cross-dataset validation to identify potential key upstream regulators. Finally, cell-based experiments were performed to verify the functional effects of DNMT1 inhibition. Changes in QDPR expression were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, and the potential chemosensitizing effect of DNMT1 inhibition in combination with platinum-based chemotherapy was further evaluated in patient-derived organoids. This study provided genetic causal evidence that locus-specific methylation influences LUAD risk, with part of this effect mediated by QDPR expression. Analyses across multiple independent datasets consistently suggested that DNMT1 may act as a key upstream epigenetic regulator contributing to the reduced expression of QDPR. Functional experiments demonstrated that DNMT1 inhibition increased QDPR expression and suppressed the proliferation and migration of LUAD cells. Drug sensitivity assays using patient-derived organoids further showed that DNMT1 inhibition exerted a significant chemosensitizing effect in the platinum low-sensitivity group. This study suggests that DNMT1 may contribute to the reduced expression of QDPR and related malignant phenotypes through epigenetic regulation. Functional and drug sensitivity experiments further support the potential of DNMT1 as a therapeutic target for improving the response to platinum-based chemotherapy in a subset of patients with LUAD. These findings provide a potential therapeutic target and offer mechanistic insights into treatment response heterogeneity and chemoresistance in LUAD.