Therapeutic potential of isothiocyanates by targeting the NRF2 pathway

Isothiocyanates have been the focus of scientific research for over fifty years. Interest in these phytochemicals intensified following the discovery of sulforaphane, an isothiocyanate found in broccoli. Early studies on sulforaphane laid the groundwork for exploring numerous other isothiocyanates, which have since been recognized as potent inducers of mammalian cytoprotective responses via the KEAP1/NRF2 pathway, alongside modulation of additional key signaling pathways. In addition to these advances in understanding the molecular regulation of this pathway and its vital role in defending against electrophilic and oxidative stress, there has been increasing interest in translating these findings into strategies to enhance human health and treat disease. This review highlights preclinical studies demonstrating the beneficial effects of isothiocyanates in activating NRF2 across various pathological conditions, including cancer, cardiovascular diseases, diabetes, liver and kidney disorders, and neurological diseases. It also discusses intervention studies related to their safety, pharmacokinetic profiles, and clinical trials. • ITCs are natural compounds derived from cruciferous vegetables with beneficial biological properties, including antioxidant, anti-inflammatory, and chemopreventive effects. • ITCs are sulfur-containing phytochemicals with the general formula R–N=C=S, generated from glucosinolate precursors through myrosinase-mediated hydrolysis. • ITCs are capable of activating NRF2-dependent cytoprotective programs primarily through modification and inhibition of KEAP1. • SFN is the most extensively studied ITC, with demonstrated efficacy in numerous preclinical models of disease, largely attributed to NRF2 activation.