Fig. 9: The graph model of the role of SLC1A5 in granulosa cells under physiological versus hyperandrogenic PCOS conditions. | Nature Communications

Fig. 9: The graph model of the role of SLC1A5 in granulosa cells under physiological versus hyperandrogenic PCOS conditions.

From: Androgens drive SLC1A5-dependent metabolic reprogramming in polycystic ovary syndrome

Fig. 9: The graph model of the role of SLC1A5 in granulosa cells under physiological versus hyperandrogenic PCOS conditions.The alternative text for this image may have been generated using AI.

In hyperandrogenic granulosa cells, elevated androgen levels directly enhance AR binding to the SLC1A5 promoter, driving its transcriptional activation and upregulating SLC1A5 expression. This hyperactivation enhances glutamine uptake, leading to excessive α-KG accumulation. The surplus α-KG interacts with histone deacetylase 5 (HDAC5), resulting in global hypoacetylation (reduced H3K14ac and H3K56ac). This epigenetic repression downregulates CYP19A1 and other folliculogenesis-related genes. Critically, CYP19A1 suppression disrupts the aromatase-mediated conversion of androgens to estrogens. Thus, a pathological feedforward loop is established: hyperandrogenism reinforces AR-driven SLC1A5 overexpression, which in turn exacerbates hyperandrogenism. This self-sustaining cycle perpetuates ovarian dysfunction in PCOS. Created in BioRender. Ye, L. (2025) https://BioRender.com/t27l890.

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