Farnesol mitigates methotrexate-induced intestinal toxicity by enhancing SIRT1, PPAR-γ, and Nrf2 signaling and attenuating Bax/cytochrome <i>c</i> /caspase-3–mediated apoptosis

Our results demonstrated that FAR markedly ameliorated the degenerative changes induced by MTX in the duodenal mucosa along with preservation of mucosal goblet cells as manifested by PAS and Alcian blue staining. Besides, FAR enhanced the antioxidant and anti-inflammatory defenses <i>via</i> up-regulated expressions of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and nuclear factor erythroid 2-related factor 2 (Nrf2) proteins. Moreover, the anti-inflammatory activity of FAR was emphasized by the substantial decrease in tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) duodenal contents in MTX-treated rats. Ultimately, FAR reduced duodenal apoptosis by down-regulating Bcl-2-associated X protein (Bax), cytochrome <i>c</i>, and cleaved caspase-3, while up-regulating B-cell lymphoma 2 (Bcl-2) expression demonstrated by the immunohistochemical investigation.<b>Conclusion:</b> FAR could protect against intestinal toxicity caused by MTX and thus increase the tolerability and adherence to prolonged MTX therapy.