MicroRNA-Mediated Rewiring of the PI3K–AKT–mTOR Axis Reveals Divergent Regulatory Networks and Metabolic Vulnerabilities in Endometriosis-Associated Ovarian Cancers (EAOCs)

Background: Endometriosis-associated ovarian cancers (EAOCs), including clear cell (OCCC) and endometrioid (EnOC) subtypes, frequently activate the PI3K/AKT/mTOR signaling axis. While genomic aberrations are well documented, the coordinated mi-croRNA (miRNA)-mediated networks governing post-transcriptional remodeling of this pathway across these subtypes remain poorly defined. Methods: We conducted an integrative in silico meta-analysis of transcriptomic and small RNA sequencing da-tasets from 135 patient tumor samples (72 OCCC, 52 EnOC) and 150 normal ovarian tissues. Differential expression analysis, dimensionality reduction (UMAP), functional enrichment, and topologically weighted miRNA–mRNA interaction networks were evaluated. Results: Both subtypes exhibited significant transcriptomic activation of core pathway machinery, including PIK3CB, and MTOR, alongside preservation of mTORC2 components. Post transcriptional concurrent downregulation of IRS1, GRB10, DDIT4, and PIK3CD under the hub miRNAs hsa-miR-30a-5p, hsa-miR-30d-5p, and hsa-miR-7-5p, suggests further refined control of the pathway. The identification of highly connected hub genes linking mTOR, MAPK, and Wnt signalling pathways within the mTOR-regulatory network suggests that pathway modulation occurs through extensive crosstalk across multiple oncogenic signalling pathways in EAOCs. Conclusions: mTOR pathway activation in EAOCs reflects not only genomic altera-tions but also durable post-transcriptional regulation. Despite subtype-specific tran-scriptomic differences, both exhibited transcriptional activation of components of the canonical PI3K/AKT/mTOR signalling axis. Pathway modulation through miRNA reg-ulatory network exhibited cross talk across oncogenic pathways and hub genes.