ZNF395, the Transcriptional Factor Linked to Viral, Inflammatory and Cancer Processes

Background/Objectives: ZNF395, also known as PBF (Human Papillomavirus Binding Factor), is an intrinsically disordered cellular protein involved in critical biological processes. These include human papillomavirus replication, the innate immune response, apoptosis induction, cell growth inhibition, the activation of autologous cytotoxic T lymphocytes, and prognosis in various cancers—all of which are associated with diseases of global significance. ZNF395 has been differentially associated with the replication of HPV8, HIV, CMV, and EBV. Notably, reports indicate contrasting behaviors across different cancer types, suggesting that it could act as a tumor suppressor or serve as a marker for poor prognosis. Furthermore, hypoxic conditions induce ZNF395 expression through the activation of HIF-1α and NF-κB, resulting in increased IL-6 and IL-8 levels in response to cellular stress, thereby promoting cell survival, migration, and angiogenesis. Methods: A non-systematic literature search was performed in PubMed (2000–2026) using keywords related to ZNF395, cancer, and viruses. Conclusions: In this work, we summarize the diverse functions performed by this single protein, challenging the traditional “one structure, one function” paradigm. Most importantly, our findings highlight that ZNF395 may hold significant potential for the diagnosis, prognosis, and treatment of cancer.