Abstract
Uterine fibroids, though benign in nature, are burdensome tumors of the myometrium and continue to weigh heavily on the landscape of women's health. They affect millions and yet receive a fraction of the therapeutic innovation afforded to malignant diseases. Despite their prevalence, the molecular underpinnings of fibroid pathogenesis have long been met with a blind eye in drug development. Recent insights, however, reveal G-protein-coupled receptor 10 (GPR10) as a central driver of fibroid growth, promoting cell survival through the PI3K/Akt and MAPK/ERK signaling pathways following REST repression. In this study, we present a rigorous, computationally guided approach to design small interfering RNAs (siRNAs) that silence GPR10 expression at the transcriptomic level. Beginning with a library of 275 siRNA candidates, we undertook a layered in-silico refinement process, combining thermodynamic assessment, secondary structure modeling and off-target filtration, to distill a shortlist of ten high-confidence molecules. These were subjected to structural docking against Argonaute 2, the catalytic engine of the RNA-induced silencing complex, revealing siRNA8 and siRNA12 as lead candidates distinguished by robust binding affinity, high predicted silencing efficacy, which was greater than 93.5%, and precise conformational fit. Subsequent molecular dynamics simulations under CHARMM-GUI/CHARMM36m force field, confirmed the structural stability and sustained silencing potential of the complex. Collectively, these findings identify GPR10 as a therapeutically actionable driver in fibroid biology and lay the groundwork for precision RNAi strategies targeting non-malignant, yet clinically neglected, hormone-dependent disorders.