Epitranscriptomic stabilization of PGRMC1 by the METTL3-IGF2BP1 axis promotes ovarian cancer progression

Ovarian cancer (OV) remains one of the most lethal gynecological malignancies, with limited effective early detection strategies and therapeutic options. Despite advances in platinum-based chemotherapy and targeted therapies, including PARP inhibitors and immune checkpoint inhibitors, treatment failure and recurrence remain common. Here, we integrated scRNA-seq data from OV tumours (GSE154600) with copy-number variation analysis and malignant transcriptional metaprogram analysis, and weighted gene co-expression network analysis to identify glycolysis-associated hub genes. We pinpointed PGRMC1 as a glycolysis-linked hub gene that is markedly upregulated in OV tissues and cell lines. Functional assays in vitro showed that PGRMC1 depletion attenuated glycolytic activity, cell proliferation, migration and invasion, whereas PGRMC1 overexpression exerted the opposite effects. In a subcutaneous xenograft model, PGRMC1 knockdown suppressed tumour growth. Mechanistically, PGRMC1 directly binds GLUT1 and maintains its protein stability by restraining MARCH8-mediated ubiquitination and proteasomal degradation. Furthermore, we demonstrate that the METTL3-IGF2BP1 axis reinforces PGRMC1 mRNA stability through m⁶A modification, thereby contributing to the pro-proliferative and pro-invasive effects of PGRMC1; notably, PGRMC1 knockdown attenuates METTL3-driven increases in proliferation and migration. Collectively, these findings delineate a METTL3-IGF2BP1-PGRMC1-GLUT1 regulatory axis that couples epitranscriptomic regulation to glycolytic rewiring in ovarian cancer and identify PGRMC1 as a glycolysis associated regulatory molecule with potential translational relevance in OV.