Retinoids, natural and synthetic signaling molecules that are structurally related to vitamin A. Compounds such as retinol, retinal, retinoic acid, retinyl esters and other derivatives are considered in the group of retinoids. Retinoids are considered the most important regulators of several essential biological functions. For example, the active derivative of retinol (metabolite of vitamin A) such as retinoic acid (RA) plays an important role in vision, cell differentiation, tissue homeostasis, apoptosis, organogenesis, regulation of immune system and in the formation of the embryonic model (1). Furthermore, AR is also considered a potent chemopreventive and tumor suppressant agent due to its apoptotic and antioxidant activity. A wide variety of animal model studies and clinical trials have demonstrated the antitumor activity of RA against several cancer types such as lymphoma, leukemia, melanoma, lung cancer, cervical cancer, kidney cancer, neuroblastoma, and glioblastoma (2 ). RA has also been shown to promote the generation of ROS, including free radicals, which drive the expression of antioxidant enzymes in rat Sertoli cells and human retinal pigment epithelial cells (3) (4). Retinoids induce their physiological effects through interaction with two distinct classes of nuclear receptors, including retinoic acid receptors (RARs) and retinoid X receptors (RXRs). These two nuclear receptors belong to members of the thyroid steroid/hormone receptor superfamily (5) (6). All-trans-retenoic acid (ATRA) and 9-cisretenoic acid (9CRA) are the two isomers of RA that act as ligands and bind to the nuclear receptors RAR and RXR. Although it is well known that 9CRA binds only with RXR, where both ATRA and 9CRA as a ligand...... at the center of the article ...... vitamin A deficient diet (VAD) to know the specific antagonist activity of RA on Nrf2. Interestingly, experimental data on western blotting of proteins in the small intestine of Nrf2 +/+ showed increased levels of Gstm5, GCLC, NQO1 and Gsta1/2 but not in Nrf2 -/- mice. Furthermore, administration of ATRA to Nrf2 +/+ mice on VAD diet showed an almost complete blockade of the increase in Gstm5, GCLC, NQO1, and Gsta1/2 proteins in the small intestine. This ARE-driven repression of gene expression strongly suggested the antagonistic role of ATRA on Nrf2. Overall, the above findings suggested that, targeting Nrf2 inhibition through RARα may become a new therapeutic approach to encounter drug resistance in tumor cells. However, further structural studies of Nrf2:RARα interactions are needed to know which domain of RARα might react with Nrf2.