Background and Objectives: Pulmonary fibrosis (PF) is a life-threatening respiratory disorder involving complex pathophysiological mechanisms such as inflammation, collagen deposition, and epithelial cell injury. Methotrexate (MTX), a chemotherapeutic and immunosuppressive agent, is frequently associated with pulmonary toxicity, representing a significant adverse effect with unpredictable outcomes. Thus, the current study investigates the possible protective effect of dulaglutide (DUL) against MTX-induced lung injury. Methods: Sixty male Wistar rats were allocated into six groups: group 1 served as a control group, group 2 received MTX (14 mg/kg/week, p.o) for 2 weeks, group 3 was treated with MTX treatment (14 mg/kg/week, p.o) prior to dexamethasone (DEXA) (0.5 mg/kg/week i.p), Groups 4-5 were treated concurrently with MTX (14 mg/kg/week, p.o) and DUL at doses of 0.05 and 0.1 mg/kg/week, s.c. and Group 6 received DUL (0.1 mg/kg/week, s.c.) only. Animals were sacrificed on day 15 for histopathological and biochemical assessments. Results: Our data demonstrated that MTX markedly increased some oxidative stress markers, inflammatory biomarkers and fibrotic and apoptotic indicators, alongside a significant decrease in Beclin-1 and Adenosine Monophosphate Activated Protein Kinase (AMPK) levels. DUL administration significantly ameliorated these alternations in a dose-dependent manner, with histopathological findings corroborating biochemical data through Hematoxylin & Eosin (H&E) and Mason's Trichrome (MTC) staining. Conclusions: DUL confers significant protection against MTX-induced pulmonary fibrosis, likely through its antioxidant, anti-inflammatory, and anti-apoptotic properties, which are associated with the restoration of total AMPK and Beclin-1 levels. This highlights its therapeutic potential in preventing drug-induced lung toxicity.
