Targeting HPV16 E5 and E6 through gene-silencing approaches: mechanisms, preclinical evidence, and therapeutic perspectives

Cervical cancer, a significant global health challenge, is strongly associated with persistent infection with high-risk human papillomavirus (HPV), particularly HPV-16. The viral oncoproteins E5 and E6 are critical to HPV-mediated carcinogenesis, as they promote cell proliferation, immune evasion, apoptosis resistance, and genomic instability. E5 contributes to tumor progression by modulating growth factor signaling and promoting cell survival. E6, on the other hand, primarily drives malignant transformation by targeting the tumor suppressor p53 for degradation. Given their pivotal roles in cervical cancer, both oncoproteins are promising therapeutic targets. Recent advancements in gene-silencing technologies have provided novel opportunities for the selective inhibition of HPV oncogenes. Small interfering RNAs (siRNAs) and CRISPR/Cas-based genome-editing systems have demonstrated significant potential in suppressing E5 and E6 expression, restoring tumor suppressor functions, inducing apoptosis, and enhancing the sensitivity of cancer cells to conventional therapies. This narrative review summarizes the biological functions of HPV16-derived E5 and E6 in cervical carcinogenesis, and discusses recent developments in gene-silencing strategies targeting these oncogenes. Furthermore, it highlights current challenges, therapeutic limitations, and future perspectives for developing targeted molecular approaches aimed at cervical cancer prevention and treatment.