Cervical cancer is a common malignant tumor of the female reproductive system, and patients with advanced and metastatic diseases have poor prognosis. It is urgent to explore novel molecular targets and regulatory mechanisms. As a core circadian rhythm factor, BMAL1 exerts tumor-suppressive or oncogenic effects in various malignancies, while its biological functions, downstream pathways and molecular mechanisms in cervical cancer remain largely unclear. In this study, human cervical cancer cell lines SiHa and HeLa, as well as nude mouse subcutaneous xenograft models were used as research systems. A series of experiments including transcriptome sequencing, protein interaction assay, ubiquitination detection, cellular functional experiments and in vivo animal assays were performed. The results demonstrated that BMAL1 knockdown markedly inhibited the proliferation, colony formation, invasion and migration of cervical cancer cells, and induced G1-phase cell cycle arrest. Transcriptome sequencing and KEGG pathway enrichment analysis identified the ERK signaling pathway as the major downstream pathway of BMAL1, and BMAL1 positively regulated the phosphorylation of key molecules in the ERK pathway. Mechanistically, BMAL1 specifically bound to FAM43B via its transactivation domain (TAD), promoted K63-linked ubiquitination of FAM43B, enhanced the protein stability of FAM43B. As a downstream effector, FAM43B unidirectionally activated the ERK signaling pathway, and no reverse regulatory loop existed between the two proteins. Silencing FAM43B significantly reversed the malignant phenotypes of cervical cancer cells. In vivo xenograft experiments further verified that BMAL1 knockdown suppressed tumor growth, reduced tumor proliferative activity. In summary, BMAL1 regulates the ERK signaling pathway by modulating the ubiquitination of FAM43B, thereby promoting the progression of cervical cancer. This study reveals a novel BMAL1/FAM43B/ERK regulatory axis and its underlying mechanism, providing potential molecular targets and experimental evidence for prognostic evaluation and targeted therapy of cervical cancer.
