Fig. 8

Working model of lipid synthesis induces by PPAR and cell cycle regulation in GCs after MLN4924 treatment. Rabbit follicular granulosa cells were isolated and treated with MLN4924, followed by transcriptomic and metabolomic sequencing. MLN4924 inhibits the intracellular neddylation process upon entering granulosa cells, impairing the PPAR signaling pathway, while also inducing apoptosis and cell proliferation in GCs. Inhibition of PPARα/γ down-regulates the target genes FABP3, FABP4, CD36, and LPL, which are involved in lipid transport, resulting in reduced fatty acid uptake. Similarly, the expression of CPT1 and CPT2 is also reduced, potentially inhibiting the process of fatty acid β-oxidation. ACSS2, responsible for linking acetate to CoA to produce acetyl-CoA, also shows reduced expression, affecting the availability of raw materials for fatty acid synthesis. Therefore, blocking neddylation within granulosa cells inhibited PPAR-mediated lipid metabolism and interfered with cell cycle progression