Citation: Rejano-Gordillo, C.M.; Marín-Díaz, B.; Ordiales-Talavero, A.; Merino, J.M.; González-Rico, F.J.; Fernández-Salguero, P.M. From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms. Int. J. Mol. Sci. 2022, 23, 14919. https://doi.org/10.3390/ ijms232314919 Academic Editors: Jose Javier Lopez, Carlos Gutierrez-Merino and José Manuel González Ros Received: 25 October 2022 Accepted: 24 November 2022 Published: 29 November 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). International Journal of Molecular Sciences Review From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms Claudia M. Rejano-Gordillo 1,2 , Beatriz Marín-Díaz 1,2 , Ana Ordiales-Talavero 1,2 , Jaime M. Merino 1,2 , Francisco J. González-Rico 1,2, * and Pedro M. Fernández-Salguero 1,2, * 1 Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, 06006 Badajoz, Spain 2 Instituto Universitario de Investigación Biosanitaria de Extremadura (INUBE) Campus de Badajoz, Avenida de la Investigación s/n, 06071 Badajoz, Spain * Correspondence: fjgonzalez@unex.es (F.J.G.-R.); pmfersal@unex.es (P.M.F.-S.) Abstract: The aryl hydrocarbon receptor (AHR) is a markedly established regulator of a plethora of cellular and molecular processes. Its initial role in the detoxification of xenobiotic compounds has been partially overshadowed by its involvement in homeostatic and organ physiology pro- cesses. In fact, the discovery of its ability to bind specific target regulatory sequences has allowed for the understanding of how AHR modulates such processes. Thereby, AHR presents functions in transcriptional regulation, chromatin architecture modifications and participation in different key signaling pathways. Interestingly, such fields of influence end up affecting organ and tissue homeostasis, including regenerative response both to endogenous and exogenous stimuli. Therefore, from classical spheres such as canonical transcriptional regulation in embryonic development, cell migration, differentiation or tumor progression to modern approaches in epigenetics, senescence, immune system or microbiome, this review covers all aspects derived from the balance between regulation/deregulation of AHR and its physio-pathological consequences. Keywords: aryl hydrocarbon receptor; epigenetics; signaling pathways; organ homeostasis 1. Introduction Intensive and uninterrupted research on aryl hydrocarbon receptor (AHR) emerged in the 1970–1980s (Figure 1). Initially, AHR was discovered in the cytoplasm of mouse liver cells. It was defined as a protein involved in the detoxification of xenobiotics due to its involvement in the induction of detoxifying enzymes such as cytochrome P450 CYP1A1 [1,2]. During the following years, the basic molecular mechanism of action of the receptor was traced, the translocation to the nucleus of the receptor was described as being dependent on its binding to exogenous ligands (generally polycyclic aromatic hydrocarbons) [3] and its relationship with the protein ARNT (aryl hydrocarbon recep- tor nuclear translocator) was uncovered [4]. Afterwards, its purification, cloning and sequencing was carried out, which allowed it to be considered a member of the super- family bHLH/PAS of transcription factors with sequences of the basic-Helix-Loop-Helix (bHLH) type of class VII [5,6], which also includes the PAS domain transcription regulators: Per (Period), ARNT and Sim (Single Minded). Finally, the production of mutant mice by gene knock-out techniques was achieved, confirming the toxicological role of the receptor: AHR-/- mice were resistant to the toxic and carcinogenic effects of xenobiotics such as dioxin TCDD (2,3,7,8-tetrachloro-dibenzo-p-dioxin) and Benzo[a]pyrene (BP) [7–9]. Those initial investigations based on AHR knock-out murine models revealed an unexpected molecular and physiological role for the receptor, with a strong implication in cell cycle, proliferation, apoptosis and carcinogenesis [10]. Int. J. Mol. Sci. 2022, 23, 14919. https://doi.org/10.3390/ijms232314919 https://www.mdpi.com/journal/ijms