Yishu Wang

Polyendocrine metabolic ovarian syndrome (PMOS) features intertwined reproductive, endocrine and metabolic defects, yet its initiating mechanisms remain incompletely understood. Here we show that an epigenetic mechanism driven by nicotinamide N-methyltransferase (NNMT) in granulosa cells contributes to disease progression in PMOS. We observe that Nnmt overexpression in mouse granulosa cells reduces histone H3 lysine 27 trimethylation (H3K27me3), leading to increased retinoic acid receptor beta (RARB) expression. RARB, in turn, amplifies ovarian androgen synthesis. The resulting androgen excess further suppresses H3K27me3, locking cells into a feedforward loop that sustains hyperandrogenism and disrupts follicle development. Pharmacological inhibition of NNMT restores H3K27me3, disrupts the RARB–androgen feedback circuit, and ameliorates both metabolic and hormonal phenotypes in PMOS models. Our findings suggest NNMT as a regulator of PMOS through metabolic and epigenetic reprogramming. The NNMT–H3K27me3–RARB–androgen axis emerges as a mechanistic nexus linking methionine and epigenetic dysregulation to PMOS pathogenesis and represents a tractable therapeutic target.

: Polycystic ovary syndrome (PCOS) is a frequent endocrine and metabolic imbalance that typically occurs in women of reproductive age. Its molecular pathophysiology is yet unknown, especially the ovarian cellular metabolic inefficiency that causes the transcriptional dysregulation of key genes linked to PCOS. Here, we discovered that one transcriptional-like regulator that causes PCOS is nuclear pyruvate kinase M2 (nPKM2). Using multiomics techniques, we show that enhanced lactylation of histone 3 on lysine residues 9 and 18 is linked to nPKM2 binding to the genome, changing the three-dimensional architecture of the genome. Genomic compartment switching, topologically associated domain fusion, and novel enhancer–promoter interactions subsequently enhance the expression of PCOS-related genes, including CYP17A1 and CYP11A1 . In mice, ectopic expression of Pkm2 in female GCs consistently presented PCOS-like traits, such as interrupted estrous cycles, hyperandrogenism, and so on. Importantly, whole-organ tracing imaging directly unfolded the number of small follicles, which increased highly in Pkm2 -tdtomato transgene mice compared with control. Furthermore, pharmacological inhibition of the nuclear accumulation of PKM2 mitigated PCOS-like symptoms in mice and restored a wild-type-like transcriptome. This study demonstrates the important function of PKM2-mediated histone lactylation in regulating the three-dimensional chromatin architecture and highlights PKM2 as a potential therapeutic target for PCOS treatment.

Polycystic ovary syndrome is the primary cause of female infertility. Growing evidence suggests that dysregulation of amino acid metabolism plays a significant role in the onset and progression. However, the underlying mechanism remains unclear. In this study, we conduct targeted metabolite profiling of human follicular fluid and granulosa cells. A significant increase in glutamine uptake is observed in patients with hyperandrogenic polycystic ovary syndrome, mediated by the upregulation of SLC1A5, a specific glutamine transporter. We find that androgen excess primarily activates SLC1A5 expression. Furthermore, SLC1A5 overexpression in female mice induces polycystic ovary syndrome-like phenotypes, including hyperandrogenism and abnormal follicle development. Additionally, the pharmacological blockade of SLC1A5 provides reproductive benefits to mice exhibiting polycystic ovary syndrome-like symptoms. Mechanistically, we show that elevated flux of Gln-derived α-ketoglutarate enhances HDAC5 expression and suppresses acetylation on histone 3 lysine residue 14 and lysine residue 56. The reduction in acetylation level is associated with the downregulation of several genes related to folliculogenesis, including CYP19A1, thereby exacerbating androgenic homeostasis imbalance. These findings indicate that androgen-induced aberrant glutamine uptake via SLC1A5 is crucial for the development and progression of polycystic ovary syndrome, suggesting pharmacological blockade of SLC1A5 as a potential therapeutic strategy.

The zinc finger CCHC-type (ZCCHC) superfamily proteins, characterized with the consensus sequence C-X₂-C-X₄-H-X₄-C, are accepted to have high-affinity binding to single-stranded nucleic acids, especially single-stranded RNAs. In human beings 25 ZCCHC proteins have been annotated in the HGNC database. Of interest is that among the family, most members are involved in the multiple steps of RNA metabolism. In this review, we focus on the diverged roles of human ZCCHC proteins on RNA transcription, biogenesis, splicing, as well as translation and degradation.