Background: Human papillomavirus (HPV)-mediated cancers, such as cervical and oropharyngeal cancers, are highly aggressive. MYC is significantly upregulated in these malignancies, contributing to poor survival, but its direct targeting is challenging due to its unique structure. Recently, BRD4 inhibitors have been shown to indirectly inhibit MYC. AZD5153, a novel and highly selective BRD4 inhibitor with bivalent binding capabilities, has passed Phase I clinical trials. However, its potential as a therapeutic option for HPV-mediated cancers has not yet been explored. Hypothesis: We hypothesize that the BRD4-MYC transcriptional axis promotes the progression of HPV-mediated tumours, and its pharmacological inhibition will enhance sensitivity to cisplatin in vivo. Methodology: We evaluated the anti-neoplastic activity of AZD5153 as monotherapy and in combination with cisplatin on the primary tumour growth in vitro using 2D and 3D HPV+ve cell line cultures, and in xenograft models in vivo. Additionally, we performed proteomic profiling using mass spectrometry to characterize the functional mechanisms through which AZD5153 exerts its anti-cancer effects. Results: We demonstrated that HPV+ve cancer cells are more susceptible to AZD5153 compared to HPV-ve cells, as inhibition of BRD4 downregulated HPV oncogenes at the transcript level. Proteomic profiling revealed upregulation of the reactive oxygen species pathway triggering ferroptosis and consequently delaying cell proliferation while increasing susceptibility to cisplatin. Furthermore, the combination of AZD5153 and cisplatin significantly impaired tumour growth in vivo (p<0.0001) compared to individual monotherapy. Conclusion: Collectively, our data demonstrate that AZD5153 could potentially serve as a novel therapeutic option for the treatment of HPV-mediated malignancies.