Nrf2 activation by the monocarbonyl curcumin derivative GO-Y015 confers cellular protection against arsenite toxicity by reducing intracellular arsenic levels

Abstract

Abstract Curcumin, a bioactive phenolic compound derived from turmeric, attenuates heavy metal toxicity, including inorganic arsenite (As(III)), via activation of the Nrf2–Keap1 signaling pathway; however, its low solubility and stability limit its bioactivity. To address these limitations, we synthesized curcumin derivatives and investigated the cytoprotective effects of a monocarbonyl analog, GO-Y015. GO-Y015 exhibited cytotoxicity comparable to curcumin at concentrations below 8 µM but significantly reduced As(III)-induced cytotoxicity. Pretreatment with GO-Y015 markedly improved cell viability under cytotoxic As(III) exposure, whereas curcumin showed minimal protective effects. Mechanistically, GO-Y015 induced robust Nrf2 activation in a concentration- and time-dependent manner, resulting in increased expression of downstream targets, including HO-1, GCLC, and MRP2. Pharmacological inhibition of Nrf2 (ML385), GSH synthesis (BSO), or MRP transporters (MK571) abolished the cytoprotective effects, indicating dependence on the Nrf2–GSH–MRP axis. Furthermore, ICP-MS analysis demonstrated that GO-Y015 significantly reduced intracellular arsenic accumulation after 2 h exposure. These findings indicate that GO-Y015 enhances arsenic detoxification and reduces cytotoxicity by promoting GSH-dependent conjugation and MRP-mediated efflux.