By RNA-sequencing and experiments in vitro using multiple ovarian cancer cell models as well as in vivo using subcutaneous xenografts assay and in situ transplantation ovarian cancer model in nude mice, we further demonstrated that RAB8A positively mediated OC progression through activating HH signaling pathway by disassociating the protein–protein complex formation of GLI and SuFu (Suppressor of Fused), which reciprocally enhanced GPR137 activity, forming a regulation loop between HH signaling and GPR137. Here, GLI1 is linked to ovarian cancer.