Aryl hydrocarbon Receptor Nuclear Translocator 2: A Forgotten Per-ARNT-Sim Transcription Factor

Aryl hydrocarbon receptor nuclear translocator 2 is a member of the basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family of transcription factors involved in responding to various environmental, metabolic, and chemical signals. Initially known for its involvement in neurodevelopment, ARNT2 is now recognized as an essential binding partner for other transcription factors, including single-minded homologs 1 and 2 (SIM1, SIM2), neuronal PAS domain protein 4 (NPAS4), hypoxia-inducible factor 1 (HIF1), and plausibly Aryl hydrocarbon Receptor (AHR) to regulate stress adaptation, synaptic plasticity, immune signaling, and energy balance pathways. The role of ARNT2 has also been implicated in a plethora of pathologies, including inflammation, cardiovascular diseases, neurological disorders, metabolic diseases, and cancers. This review summarizes the current knowledge of ARNT2's structure, regulation, interacting partners, and its toxicopathological significance. A better understanding of ARNT2 biology may open new avenues for its characterization as a molecular target and designing novel therapeutic strategies across multiple diseases.