p62/SQSTM1 (p62) and neighbor of BRCA1 gene 1 (NBR1) are two important cargo receptors involved in selective autophagy. While p62 is known to safeguard cells against the toxic effects of the environmental toxicant methylmercury (MeHg), the specific functions of p62 and NBR1 in MeHg-exposed cells remain unclear. In this study, we aimed to elucidate the distinct roles of p62 and NBR1 in conferring protection against cytotoxicity induced by MeHg. We found that MeHg increased both the mRNA and protein levels of p62 while decreasing those of NBR1. Upon exposure to MeHg, p62-knockout (KO) cells exhibited an approximately 30 % reduction in cell viability compared to wild-type (WT) cells
however, no such reduction was observed in NBR1KO cells. Additionally, p62KO cells exhibited a 1.5-fold increase in intracellular mercury (Hg) concentration compared to the WT following MeHg exposure, whereas NBR1KO cells had Hg levels comparable to those of WT cells. Upon exposure to MeHg, Nrf2 signaling activation was significantly reduced in p62KO cells compared to that in WT cells, whereas NBR1KO cells displayed Nrf2 activation levels similar to those of WT cells. Overall, these results suggest that p62, rather than NBR1, plays a crucial role in mitigating MeHg-induced cytotoxicity by reducing intracellular Hg levels through the activation of the Nrf2 signaling pathway.