Ferulic acid abrogates methotrexate-induced pulmonary injury by reducing inflammation and endoplasmic reticulum stress in rats

Alemdar, Nihal Turkmen and Demir, Selim and Yulug, Esin and Erdogan, Nadire Sevdenur and Demir, Elif Ayazoglu and Mentese, Ahmet and Aliyazicioglu, Yuksel (2026) Ferulic acid abrogates methotrexate-induced pulmonary injury by reducing inflammation and endoplasmic reticulum stress in rats. PHYSIOLOGY INTERNATIONAL, 113 (3). pp. 457-472. ISSN 2498-602X

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Abstract

Background: The methotrexate (MTX) is employed in the treatment of various malignancies, including breast cancer and lymphoma, as well as chronic inflammatory diseases, but high doses can cause pulmonotoxicity. Ferulic acid (FEA) is a phenolic compound that has become a promising candidate for oxidative stress (OS) related diseases over the past few years because of its striking range of biological activities. The aim of this experimental study was to investigate the protective effects of FEA against MTX-induced pulmonary toxicity via the potential mechanisms of OS, inflammation, endoplasmic reticulum stress (ERS) and sirtuin 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signalling. Methods: The rats were administered FEA (50 and 100 mg kg1 , p.o.) on consecutive days for a period of seven days. Meanwhile, MTX (20 mg kg1 , i.p.) was administered as a single injection on the second day of the study. At the conclusion of the treatment period, samples of lung tissue were examined in terms of histopathological findings, while the remaining tissue samples were evaluated in terms of OS, inflammation, ERS, SIRT1/Nrf2 pathway and apoptosis for further colorimetric analysis. Results: The administration of MTX suppressed the SIRT1/Nrf2 signalling pathway, resulting in histopathological findings characterised by a dramatic increase in OS, inflammation and ERS levels in the lung tissue. However, the FEA treatments attenuated these harmful effects by modulating the SIRT1/Nrf2 signalling pathway. Conclusion: Taken together, these results suggest that FEA may be protective against MTX-induced pulmonary toxicity. Nevertheless, further studies are required to elucidate the precise mechanisms of the protective effects of FEA.

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