4-Hexylresorcinol Attenuates Ethanol-Induced Hepatic and Pancreatic Injury by Modulating Metabolic Dysfunction and Endoplasmic Reticulum Stress

Background/Objectives: Chronic ethanol (EtOH) consumption is a major cause of metabolic dysfunction and multi-organ injury, particularly in the liver and pancreas. Because oxidative stress and endoplasmic reticulum (ER) stress are central mechanisms in both organs, this study evaluated the protective efficacy of 4-hexylresorcinol (4HR) against EtOH-induced hepato-pancreatic injury. Methods: Male C57BL/6J mice (6 weeks old) were assigned to four groups (n = 10/group): control, EtOH, EtOH + 4HR (5 mg/kg), and EtOH + 4HR (10 mg/kg). After a 1-week adaptation period, mice were fed a liquid EtOH diet for 5 weeks. Glucose tolerance, fasting glucose, serum insulin, and insulinogenic index were assessed. Liver and pancreas were analyzed by histology, immunohistochemistry, Western blotting, periodic acid-Schiff staining, Oil Red O staining, and malondialdehyde assay. Results: Chronic EtOH exposure impaired glucose homeostasis, reduced the insulinogenic index, increased hepatic inflammation and ALT levels, depleted hepatic glycogen, elevated pancreatic lipid peroxidation, and upregulated GADD153 (CHOP) expression in both the liver and pancreas. 4HR administration, particularly at 10 mg/kg, attenuated several of these alterations. 4HR treatment was associated with reduced hepatic inflammatory changes and ALT elevation, decreased pancreatic malondialdehyde levels, and suppressed GADD153 expression in both organs. Although PAS staining in the 4HR-treated group showed a qualitative tendency toward increased hepatic glycogen deposition, quantitative analysis did not demonstrate significant recovery relative to the EtOH group. Conclusions: 4HR showed protective effects against several aspects of chronic EtOH-induced hepatic and pancreatic injury, including hepatic inflammation, pancreatic lipid peroxidation, and ER stress-related GADD153 expression. However, quantitative PAS analysis did not support significant restoration of EtOH-induced hepatic glycogen depletion by 4HR. These findings suggest that 4HR may serve as a potential multi-organ protective agent against alcohol-induced inflammatory, oxidative stress-, and ER stress-related injury, although its effect on hepatic glycogen metabolism remains limited under the present experimental conditions.