AP2/ERF transcription factors (TFs) constitute a large, plant-specific family that acts as a central hub integrating developmental and environmental signals to modulate the biosynthesis of secondary metabolites. These compounds, including terpenoids, phenolic compounds, and alkaloids, are vital for plant survival and are of immense value to human health and industry. This review provides a comprehensive synthesis of the molecular mechanisms by which AP2/ERF TFs regulate these crucial metabolic pathways. We systematically classify and dissect their regulatory modes, including direct binding to cis-elements (e.g. GCC-box, CE1, and DRE/CRT), indirect control via upstream signaling cascades, co-regulation through physical interactions with other TF families (e.g. MYB, bHLH, WRKY), and feedback regulation. We present numerous case studies across diverse plant species, highlighting both conserved principles and species-specific adaptations in the control of high-value natural products like artemisinin, tanshinones, anthocyanins, and nicotine. Furthermore, we discuss the emerging roles of AP2/ERF TFs in metabolic engineering and synthetic biology, and outline future research directions, emphasizing the application of multi-omics and CRISPR/Cas9 technologies to unravel and engineer these complex regulatory networks for targeted overproduction of valuable phytochemicals.

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