APE1/REF-1 is a protein with two domains: an endonuclease domain involved in DNA repair and a redox domain that regulates transcription factors such as AP-1, NF-κB, HIF-1α, and STAT3. These factors are involved in cellular processes like cell growth, inflammation, and angiogenesis, as well as cancer. APE1/REF-1 is overexpressed in various cancers, including lung, colon, ovarian, prostate, and breast cancer, and is associated with more aggressive tumor phenotypes and worse prognosis. Both domains of APE1/REF-1 are essential for cancer cells, with the redox domain playing a key role in regulating transcription factors. APE1/REF-1 is involved in essential cancer processes such as proliferation, invasion, inflammation, angiogenesis, and resistance to cell death. Its activity in these hallmarks suggests that targeting APE1/REF-1 could be a promising therapeutic approach. Recent studies have shown that APE1/REF-1 also regulates onco-miRNAs, which are involved in RNA metabolism, transport, and cancer-related processes. APE1/REF-1 is involved in the processing of damaged RNA in chemoresistant phenotypes and the degradation of oxidized RNA. It also interacts with genes involved in DNA and mRNA metabolism and DNA damage response. These interactions are associated with poor prognosis in cancer patients. APE1/REF-1 modulates transcription by enhancing gene transcriptional fluctuation and preventing transcription through negative DNA supercoiling. However, this mechanism accelerates transcription upon DNA repair, maintaining mean expression levels. This process, known as "discordant transcription through repair" (DiThR), regulates gene expression homeostasis. APE1/REF-1 is also related to G4-mediated gene transcription, which involves the formation and function of G-quadruplexes (G4) in DNA. These findings highlight the multifaceted role of APE1/REF-1 in cancer development and progression.APE1/REF-1 is a protein with two domains: an endonuclease domain involved in DNA repair and a redox domain that regulates transcription factors such as AP-1, NF-κB, HIF-1α, and STAT3. These factors are involved in cellular processes like cell growth, inflammation, and angiogenesis, as well as cancer. APE1/REF-1 is overexpressed in various cancers, including lung, colon, ovarian, prostate, and breast cancer, and is associated with more aggressive tumor phenotypes and worse prognosis. Both domains of APE1/REF-1 are essential for cancer cells, with the redox domain playing a key role in regulating transcription factors. APE1/REF-1 is involved in essential cancer processes such as proliferation, invasion, inflammation, angiogenesis, and resistance to cell death. Its activity in these hallmarks suggests that targeting APE1/REF-1 could be a promising therapeutic approach. Recent studies have shown that APE1/REF-1 also regulates onco-miRNAs, which are involved in RNA metabolism, transport, and cancer-related processes. APE1/REF-1 is involved in the processing of damaged RNA in chemoresistant phenotypes and the degradation of oxidized RNA. It also interacts with genes involved in DNA and mRNA metabolism and DNA damage response. These interactions are associated with poor prognosis in cancer patients. APE1/REF-1 modulates transcription by enhancing gene transcriptional fluctuation and preventing transcription through negative DNA supercoiling. However, this mechanism accelerates transcription upon DNA repair, maintaining mean expression levels. This process, known as "discordant transcription through repair" (DiThR), regulates gene expression homeostasis. APE1/REF-1 is also related to G4-mediated gene transcription, which involves the formation and function of G-quadruplexes (G4) in DNA. These findings highlight the multifaceted role of APE1/REF-1 in cancer development and progression.