Epirubicin Alters Pancreatic Autophagy and Insulin Synthesis Through a Zinc-Dependent Mechanism

Epirubicin (EPI) can cause metabolic side effects, including chemotherapy-related diabetes, partly through oxidative stress that disrupts zinc (Zn) homeostasis and impairs autophagy. This study investigated the effects of EPI on Zn regulation and autophagy in the pancreas, as well as the modulatory role of N-acetylcysteine (NAC). Rats received EPI (9.6 mg/kg) by intraperitoneal injection (i.p.) followed 1 h later by NAC (50 or 300 mg/kg, i.p.). Glucose homeostasis was assessed using the Homeostatic Model Assessment (HOMA-IR), and β-cell function was assessed using HOMA-β levels. Plasma insulin levels, as well as insulin, proinsulin, beclin, autophagy-related proteins (ATG5), Microtubule-Associated Protein 1 Light Chain 3 (LC3), phosphorylated Akt (p-Akt), mechanistic target of rapamycin complex 1 (mTOR1), cleaved caspase-3, Zrt/Irt-like Protein 10 (ZIP10), and the proliferation marker Ki-67 in pancreatic tissue, were measured using commercial ELISA kits. Total oxidant status (TOS) and total antioxidant status (TAS) were measured using commercial colorimetric assay kits, and the oxidative stress index (OSI) was calculated. Zn levels in pancreatic tissue and plasma samples were measured using a colorimetric method. Morphological changes in the pancreas were assessed by hematoxylin and eosin staining. As a result, in the EPI group, oxidative stress and ZIP10 levels increased, whereas Zn levels decreased, as well as pancreatic autophagy, proliferation, and insulin synthesis increased. Oxidative stress decreased in both the EN-50 and EN-300 groups, with a more pronounced decrease in the EN-300 group. Furthermore, in the EN-300 group, pancreatic Zn, ZIP10, autophagy, and proliferation levels decreased, whereas mTOR1 levels increased. The pancreatic insulin synthesis observed in the EN-50 group was not observed in the EN-300 group. In conclusion, the increased autophagy observed in the Epi group may reflect an adaptive response to oxidative stress. The effects of NAC on oxidative stress may be dose-dependent, and high-dose NAC administration may suppress EPI-induced autophagy via mTOR1-mediated signaling. Furthermore, the relationship among Zn levels, autophagy, and insulin synthesis observed in the experimental groups may contribute to a better understanding of EPI-associated diabetogenic alterations.