Thymopentin alleviates premature ovarian failure in mice by activating YY2/Lin28A and inhibiting the expression of let‐7 family microRNAs

Abstract Objective Thymopentin (5TP) significantly improved typical murine premature ovarian failure (POF) symptoms induced by a high‐fat and high‐sugar (HFHS) diet. However, its effect and mechanism remain unclear. Materials and methods RNA‐Seq was used to detect the differentially expressed genes among each group. HFHS‐induced POF mouse model was generated and injected with siRNA using Poly (lactic‐co‐glycolic acid) (PLGA) as a carrier. Results RNA‐Seq suggested that 5TP promoted the expression of Yin Yang 2 (YY2) in mouse ovarian granulosa cell (mOGC) of HFHS‐POF mice. Luciferase reporter assay indicated that 5TP promoted the binding of YY2 to the specific sequence C(C/T)AT(G/C)(G/T) on the Lin28A promoter and promoted Lin28A transcription and expression. We continuously injected PLGA‐cross‐linked siRNA nanoparticles targeting YY2 into HFHS‐POF mice (siYY2@PLGA), which significantly reduced the therapeutic effect of 5TP. siYY2@PLGA injection also significantly attenuated the upregulation of Lin28a expression in mOGCs induced by 5TP and enhanced the expression of let‐7 family microRNAs, thereby inhibiting the proliferation and division of mOGCs. qPCR results showed that there was a significant difference in the expression levels of exosome‐derived Yy2 mRNAs between POF patients and normal women, and that there was a specific correlation between the expression level of exosome‐derived Yy2 and the peripheral concentrations of the blood hormones pregnenolone, progesterone and oestradiol. Conclusions Thymopentin promotes the transcriptional activation of Lin28A via stimulating transcription factor YY2 expression, inhibits the activity of let‐7 family microRNAs and alleviates the ageing of ovarian granulosa cells, ultimately achieving a therapeutic effect on POF in mice.