SOX3 facilitates granulosa cell proliferation and suppresses cell apoptosis through modulating PI3K/AKT pathway by targeting SPP1.

Folliculogenesis is a crucial process for production functional female gametes in mammals. The imbalance of apoptosis and proliferation of ovarian granulosa cells has been identified as an important cause for abnormal folliculogenesis. Sex-determining region Y-box protein 3 (SOX3), belonged to the SRY-box transcription factor family, is involved in follicular development. Nonetheless, the regulatory mechanisms of SOX3 and ovarian granulosa cell state remains poorly understood. In this study, we constructed stable overexpression and knockdown SOX3 ovarian granulosa cell lines. We observed that SOX3 can promote the proliferation and inhibit the apoptosis of KGN cells. Comparative transcriptome analysis revealed that 1,717 genes exhibited up-regulation and 1,240 genes displayed down-regulation in OE-SOX3 compared to OE-NC. Further pathway analysis demonstrated that the DEGs were associated with many biological processes, particularly the PI3K/AKT signaling pathway. Moreover, we discovered that SOX3 facilitates the proliferation and inhibits the apoptosis of KGN cells through PI3K/AKT signaling pathway. Finally, we unveiled that SOX3 can bind to the promoter of SPP1 and activate the promoter activity, which in turn up-regulates the PI3K/AKT signaling pathway. The results were also confirmed in sox3 knockout zebrafish. Altogether, our findings demonstrated that SOX3 facilitates granulosa cell proliferation and suppresses apoptosis by activating the SPP1/PI3K/AKT pathway, which might be implicated in improving female fecundity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-025-05797-4.