Usnic acid suppresses inflammation and endoplasmic reticulum stress in a methotrexate-induced pulmonary toxicity model via modulating Nrf2 pathway

Abstract

Pulmonary toxicity represents a significant adverse effect of methotrexate (MTX), characterised by increased oxidative stress (OS) and inflammation. This study focused on revealing the therapeutic role of usnic acid (UA) against MTX-induced lung injury through biochemical and histological approaches by involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. A single dose of MTX was administered to rats to induce pulmonary toxicity, and the therapeutic effect of UA was investigated with two different doses (5 and 10 mg/kg). The administration of UA treatments resulted in a significant reduction in the levels of MTX-induced OS, inflammation, endoplasmic reticulum stress and apoptosis in the lungs of rats. The administration of UA treatments was found to ameliorate the morphological damage induced by MTX in the lungs of rats. Furthermore, the administration of a particularly high dose of UA resulted in a significant increase in the levels of Nrf2 and HO-1 proteins in rats compared to those treated with MTX. These findings provide new insight and the first experimental evidence that UA may serve as an effective therapeutic agent in alleviating MTX-induced acute pulmonary toxicity by regulating the Nrf2/HO-1 pathway.