NFE2L3 is an endoplasmic reticulum membrane-anchored bZIP transcription factor that translocates to the nucleus to regulate gene expression in response to cellular stress 1. As a member of the Cap'n'Collar transcription factor family, it functions as a DNA-binding transcription factor regulating antioxidant responses, inflammatory pathways, and cell cycle processes 1. While originally identified for erythroid-specific gene regulation, NFE2L3's primary contemporary relevance is in cancer biology. Mechanistically, NFE2L3 promotes malignant behavior through multiple pathways. It activates Wnt/β-catenin signaling in hepatocellular carcinoma, promoting epithelial-mesenchymal transition (EMT) and cell proliferation 2. In lung adenocarcinoma, METTL3-stabilized NFE2L3 mRNA maintains cancer stem cell stemness and therapy resistance via WNT pathway activation 3. In renal cancer, NAT10-mediated ac4C acetylation stabilizes NFE2L3 mRNA, activating the AKT/GSK3β/β-catenin signaling cascade 4. Additionally, BMP2-induced NFE2L3 expression in bladder cancer-associated fibroblasts promotes tumor angiogenesis through WNT5A regulation 5. Clinically, NFE2L3 overexpression associates with poor prognosis across multiple cancers including bladder, kidney, hepatocellular, and lung cancers 671. It represents a potential biomarker and therapeutic target for cancer treatment.