miR-148a-3p is elevated in serum of PCOS women and modulates ALDH1A3-retinoic acid signaling to reduce estrogen synthesis in granulosa-like cells.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder with substantial reproductive and metabolic consequences, yet its molecular mechanisms remain incompletely understood. This study investigated circulating microRNAs (miRNAs) as potential regulators of ovarian steroidogenesis contributing to PCOS pathophysiology. Serum samples from 42 Turkish non-diabetic women with PCOS and 42 age-matched healthy controls were analyzed in a case-control design integrating small RNA sequencing with subgrouping based on steroidogenic characteristics. Differentially expressed miRNAs were subsequently examined in adrenal and ovarian cell models, including HGL5, OVCAR-3, and KGN granulosa cells, using miRNA mimics to assess transcriptional effects and estradiol synthesis in vitro. Serum profiling identified miR-148a-3p as significantly upregulated in hyperandrogenic PCOS. Functional assays demonstrated that miR-148a-3p enhances expression of aldehyde dehydrogenase 1A3 (ALDH1A3), promoting retinoic acid synthesis and suppressing estradiol production in granulosa cells. Luciferase reporter studies confirmed transcriptional activation of ALDH1A3 by miR-148a-3p. These findings position miR-148a-3p as a possible regulator of ovarian steroidogenesis in PCOS. By driving ALDH1A3-mediated retinoic acid production and reducing estrogen synthesis, miR-148a-3p may contribute to the hyperandrogenic phenotype. The miR-148a-3p-ALDH1A3 axis offers a promising avenue for biomarker development and therapeutic targeting in PCOS.