Cinnamaldehyde down-regulates HPV oncoproteins E6 and E7 expression and enhances anti-cervical cancer activity via covalent binding to RPS16

The mortality rate among patients with cervical cancer (CVC) is a significant concern among female malignancies, posing a substantial threat to women's well-being. Human papillomavirus (HPV), a non-enveloped double-stranded DNA virus with epithelial characteristics, has been identified as a causative factor in CVC, primarily through persistent high-risk HPV infection. This study investigated the potential anti-CVC effects of CA in vitro and in vivo using the HPV-positive CVC cell line HeLa according to colony formation and cell wound healing, target fishing, molecular docking, network pharmacology analysis, cellular thermal shift, RNA interference and quantitative reverse transcription-polymerase chain reaction, immunofluorescent staining, immunohistochemical staining and xenografts assays. We found that CA could impede proliferation, induce cell cycle arrest, and prompt apoptosis by inhibiting the PI3K/Akt signaling pathway. Target fishing and molecular imaging utilizing an alkynyl-CA probe revealed the ribosomal protein S16 (RPS16) as a CA target, mediating the degradation of E6 and E7 proteins. The covalent binding of CA to RPS16 led to alterations in its stability. These findings highlight the huge potential of CA in designing and developing lead compounds for this patient population and suggest RPS16 as a novel therapeutic target.