FDFT1 is associated with ovarian reserve and regulates proliferation and steroidogenesis in the human granulosa cell line KGN via the AKT/mTOR signaling pathway.

Diminished ovarian reserve (DOR) leads to decreased ovarian endocrine function and reduced fertility in women, contributing to infertility. Dysregulated lipid metabolism can impair normal follicular development by interfering with cholesterol metabolism and hormone synthesis, thereby contributing to DOR. Farnesyl-diphosphate farnesyltransferase 1 (FDFT1), a key enzyme in the cholesterol biosynthesis pathway, remains poorly understood in DOR pathogenesis. This study investigated the relationship between FDFT1 expression in human granulosa cells (GCs) and ovarian reserve, and further examined the effects of FDFT1 on the biological functions of KGN cell line in vitro. The results showed that FDFT1 expression was significantly downregulated in GCs from DOR patients and was associated with elevated FSH and reduced AMH and AFC levels. In vitro, FDFT1 knockdown inhibited granulosa cell proliferation, induced cell cycle arrest, and promoted apoptosis; it also reduced intracellular steroid hormone synthesis. Mechanistically, FDFT1 knockdown suppressed the AKT/mTOR pathway. Notably, pharmacological activation of this pathway effectively reversed KGN cell dysfunction induced by FDFT1 knockdown. In conclusion, FDFT1 shows promise as a novel biomarker and therapeutic target for evaluating granulosa cell function and ovarian reserve, providing new molecular insights into DOR pathogenesis.