2-Chloroethanol induces hepatic toxicity by disrupting endoplasmic reticulum homeostasis ameliorated by dimethyl sulfoxide.

2-Chloroethanol (2CE), a metabolite of ethylene oxide, vinyl chloride, and 1,2-dichloroethene, induces acute liver injury, but its mechanisms remain poorly defined. In this study, we demonstrate that 2CE disrupts endoplasmic reticulum (ER) homeostasis and activates unfolded protein response (UPR) signaling in both mouse liver and H4IIEC3 hepatoma cells. While in vivo eIF2α-CHOP signaling predominated, all three canonical UPR branches-IRE1α-XBP1s, PERK-eIF2α-CHOP, and ATF6-were activated in vitro. Notably, 2CE-induced XBP1s expression was transient, whereas pro-apoptotic UPR signaling persisted, suggesting an imbalance. Among several ER stress modulators tested, only dimethyl sulfoxide (DMSO) significantly improved cell viability and increased the 24-h LD₅₀ of 2CE in mice. Mechanistically, DMSO sustained XBP1s expression while reducing eIF2α phosphorylation, CHOP expression, and cleaved ATF6, indicating a rebalancing of UPR signaling toward a pro-survival state. Pharmacologic inhibition of IRE1α with 4μ8C abolished the protective effect of DMSO, suppressed XBP1s, and elevated cleaved caspase-3, confirming the critical role of the IRE1α-XBP1s axis in cytoprotection. These findings highlight UPR signaling dynamics as a central feature of 2CE-induced ER stress and identify IRE1α-XBP1s as a promising therapeutic target.