Insights into the protective role of trigonelline in 5-fluorouracil–induced lung injury: targeting oxidative stress, inflammation, and apoptosis

5-Fluorouracil (5-FU) is an effective chemotherapeutic agent; however, its clinical use is frequently limited by toxicity in normal tissues, including the lungs. This study investigated the prophylactic protective effect of trigonelline (TRIG), a naturally occurring alkaloid, against 5-FU-induced pulmonary injury, with particular emphasis on oxidative stress, inflammation, and apoptosis. Twenty-eight male Sprague-Dawley rats were randomly assigned to four groups (n = 7): Control, TRIG, 5-FU, and TRIG + 5-FU. TRIG (50 mg/kg) was administered orally for seven consecutive days before a single intraperitoneal injection of 5-FU (100 mg/kg). Pulmonary injury was evaluated using biochemical, histopathological, and immunohistochemical analyses. Administration of 5-FU reduced body weight gain, increased relative lung weight, disrupted oxidant–antioxidant homeostasis, and induced histopathological alterations in lung tissue. These changes were accompanied by increased TNF-α, NFκB-p65, MAPK, and Bax expression together with decreased Bcl-2 expression, indicating activation of inflammatory and apoptotic pathways. Prophylactic TRIG administration restored oxidant–antioxidant balance, suppressed TNF-α, NFκB-p65, MAPK, and Bax expression, increased Bcl-2 expression, and markedly improved histopathological findings, demonstrating attenuation of oxidative stress, inflammation, and apoptosis. TRIG protects against 5-FU-induced pulmonary injury through coordinated antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. These findings provide experimental evidence supporting the prophylactic use of TRIG as a potential adjunctive strategy for reducing chemotherapy-associated pulmonary toxicity. Further experimental and preclinical studies are warranted to validate its efficacy, elucidate its molecular targets, and evaluate its translational potential. © 2026 Informa UK Limited, trading as Taylor & Francis Group.