m6A-Related SNPs in endometriosis and ovarian cancer: implications for chemoresistance and therapeutic targeting
Ovarian cancer (OC) is highly lethal, largely due to late diagnosis and chemoresistance. Endometriosis (EM) increases the risk of specific OC subtypes, but the molecular connection between the two diseases is still unclear. m6A RNA methylation may contribute to tumor progression and therapy resistance. This study investigated m6A-associated genetic variants and their regulatory roles in OC and EM, with a focus on mechanisms of cisplatin resistance. GWAS summary statistics were combined with m6A-associated variants from the RMVar database to identify disease-related m6A-SNPs. HaploReg was used for eQTL analysis. Single-cell RNA sequencing (scRNA-seq) data from chemotherapy-treated OC samples were analyzed to identify resistant tumor subpopulations and microenvironmental changes. TCGA data provided external validation, including drug sensitivity correlations. Functional assays were performed using LDHB overexpression and knockdown models. We identified 49 m6A-SNPs associated with OC and 110 associated with EM. Several showed eQTL effects on genes involved in immune regulation, oxidative stress, and cell adhesion. scRNA-seq revealed distinct drug-resistant epithelial subpopulations enriched for IFITM2, HLA-DQB1, and metabolic regulators, along with increased infiltration of macrophages, fibroblasts, and B-cell lineages. TCGA pharmacogenomic analysis demonstrated a strong negative correlation between LDHB expression and cisplatin sensitivity. Functional experiments showed that LDHB overexpression promoted cisplatin resistance, enhanced migration, and reduced apoptosis, whereas LDHB knockdown had opposite effects. This study identifies m6A-related SNPs as important regulatory factors shared between OC and EM. By integrating genetic, transcriptomic, and functional data, we highlight immune and metabolic pathways-especially those involving LDHB, IFITM2, and HLA-DQB1-as key contributors to cisplatin resistance. These findings provide potential therapeutic targets and a framework for understanding m6A-associated mechanisms in ovarian cancer progression. Further in vivo studies are needed to validate the direct effects of specific m6A-SNPs.