LRRC46 regulates bovine granulosa cell functions via the COL8A1-mediated EGFR/PI3K/AKT signaling pathway

Bovine antral follicle count (AFC) is closely associated with ovum pick-up and in vitro embryo production (OPU-IVEP) efficiency in cattle. However, the molecular basis underlying inter-individual variation in AFC remains poorly defined. This study aimed to identify key regulatory genes in the ovarian microenvironment and elucidate their mechanisms. Using transcriptome sequencing (RNA-seq) of peripheral blood from Yanbian Yellow Cattle with stable high-versus low-AFC phenotypes, we identified 280 differentially expressed genes (DEGs). Among them, LRRC46 was significantly downregulated in the low-AFC group and was selected as a candidate regulator. Functionally, LRRC46 overexpression in bovine granulosa cells (bGCs) significantly promoted cell proliferation and steroidogenesis (E2 and P4 secretion) while inhibiting apoptosis. Mechanistically, our data suggest that LRRC46 upregulates Type VIII collagen (COL8A1), which subsequently facilitates EGFR phosphorylation and activates the downstream PI3K/AKT signaling cascade. Notably, the EGFR inhibitor Afatinib completely abolished the beneficial effects of LRRC46. In conclusion, this study reveals a novel LRRC46-COL8A1-EGFR axis that regulates bGCs function, suggesting that LRRC46 may serve as a potential regulator of reproductive performance, pending further validation.