CREB3L4 is a transcription factor belonging to the CREB/ATF family that functions as a key regulator of cellular stress responses and cancer progression. As a member of the CREB3 protein family, CREB3L4 is activated through regulated intramembrane proteolysis during endoplasmic reticulum stress and plays a pivotal role in the unfolded protein response 1. The protein binds DNA sequence-specifically and regulates transcription of target genes including VEGFA and PCNA 23. Mechanistically, CREB3L4 directly interacts with the androgen receptor, enhancing its binding to androgen response elements and promoting expression of AR target genes 4. In male germ cells, CREB3L4 is highly expressed in postmeiotic stages and contributes to normal spermatogenesis, though its loss does not completely compromise fertility 5. Clinically, CREB3L4 is significantly implicated in multiple cancers. Elevated CREB3L4 expression correlates with poor prognosis in gastric cancer, where it promotes angiogenesis and tumor progression via VEGFA transcriptional activation 2. In breast cancer, CREB3L4 promotes proliferation through PCNA upregulation and p27 degradation via the SKP2 axis 36. Mendelian randomization studies identified genetically elevated CREB3L4 levels as causally associated with increased prostate cancer risk 7, supporting its therapeutic potential as a cancer treatment target.