2-Chloroethanol Induces Hepatic Toxicity by Disrupting Endoplasmic Reticulum Homeostasis Ameliorated by Dimethyl Sulfoxide

2-Chloroethanol (2CE), a metabolite of ethylene oxide (EO), vinyl chloride (VC), and 1,2-dichloroethene (1,2-DCE), has an unclear toxic mechanism, complicating effective treatment of poisoning. This study examined the impact of acute 2CE exposure on endoplasmic reticulum (ER) homeostasis in liver cells. A single intraperitoneal injection of 130 mg/kg 2CE (approximately LD50) in mice caused severe liver damage and steatosis, along with increased ER stress and activation of the unfolded protein response (UPR) and autophagy. In H4IIEC3 rat hepatocytes, 2CE activated all three UPR pathways—IRE1, PERK, and ATF6—at both the gene and protein levels, and induced lysosomal accumulation, lipid droplet formation, and apoptosis. Among chemical chaperones tested, dimethyl sulfoxide (DMSO, 0.1–0.6%) showed the most potent therapeutic effects, reducing misfolded protein accumulation, alleviating ER stress, and suppressing apoptosis, even when autophagy was inhibited. These findings reveal that 2CE disrupts protein and lipid homeostasis in hepatocytes and highlight DMSO as a promising therapeutic agent for 2CE-induced toxicity.