Geraniol Mitigates Cytarabine‐Induced Hepatotoxicity in Mice via PI3K/AKT‐Mediated NRF2 Activation

Hepatotoxicity, principally driven by oxidative stress and inflammation, is a notable adverse effect of cytarabine, a chemotherapeutic drug extensively utilized in cancer therapy. This research examines the hepatoprotective properties of the natural monoterpenoid geraniol (GNL) in a murine model of cytarabine-induced hepatic injury, emphasizing its influence on oxidative stress, inflammation, and critical signaling pathways like PI3K/AKT and NF-κB. The animals were categorized into four groups (n = 6). Groups II and III were administered cytarabine at a dosage of 0.3 mg/kg (i.p.) for a duration of 7 days. Group III received a pre-treatment of GNL (20 mg/kg) via intraperitoneal injection for 7 days prior to administration of cytarabine. Group IV was administered GNL only at a dosage of 20 mg/kg for 7 days. Group I served as a control. Cytarabine administration led to increased liver damage markers, including elevated blood ALT and AST levels, alongside heightened oxidative stress as seen by increased malondialdehyde (MDA) levels and diminished antioxidant enzyme activity (SOD and CAT). Moreover, cytarabine-induced inflammation was marked by elevated levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and the activation of the NF-κB signaling pathway, evidenced by enhanced nuclear translocation of p65. GNL therapy markedly alleviated these effects, lowering blood ALT and AST levels while reestablishing antioxidant equilibrium by diminishing MDA levels and augmenting SOD and CAT activity. Histopathological examination demonstrated significant improvement in liver tissue structure, characterized by reduced hepatocyte degradation and inflammatory infiltration. GNL suppressed NF-κB activation while promoting PI3K/AKT signaling, resulting in decreased pro-inflammatory cytokines and less liver damage. These findings underscore the potential of GNL as a hepatoprotective drug against cytarabine-induced hepatotoxicity, mediated by its antioxidant and anti-inflammatory effects through modulation of the PI3K/AKT and NF-κB pathways. Future research should investigate its therapeutic potential in alleviating chemotherapy-induced liver damage.