Background: Doxorubicin is an effective antineoplastic agent, but its use is constrained by off-target toxicities, including acute liver injury driven by mitochondrial dysfunction, oxidative stress, sterile inflammation, and redox-sensitive signaling pathways. Exenatide, a glucagon-like peptide-1 receptor agonist, exerts antioxidant and anti-inflammatory effects in several experimental liver injury models, but its role in doxorubicin-induced hepatic injury has not been investigated to our knowledge. This study evaluated whether exenatide attenuates acute doxorubicin-induced hepatic injury and examined whether the observed biochemical changes are consistent with modulation of oxidative stress and SIRT1-HMGB1/NF-κB-related signaling. Methods: Male Wistar albino rats were allocated to four groups (n = 7/group): control, exenatide, doxorubicin, and exenatide + doxorubicin. Exenatide (10 µg/kg/day, intraperitoneally) was administered for seven days. Doxorubicin was given intraperitoneally on days 5-7 at a cumulative dose of 18 mg/kg. The pretreatment design was used to test preventive attenuation rather than reversal of established injury. Hepatic injury-associated enzyme activities, serum HMGB1, hepatic SIRT1, NF-κB, TNF-α, IL-6, IL-10, malondialdehyde, glutathione, total antioxidant status, total oxidant status, nitric oxide, and hepatic 99mTc-pyrophosphate uptake were assessed. Results: Doxorubicin substantially increased intrahepatic ALT and AST activities, serum HMGB1, hepatic NF-κB, TNF-α, IL-6, malondialdehyde, total oxidant status, nitric oxide, and hepatic 99mTc-pyrophosphate uptake, while reducing SIRT1, IL-10, glutathione, and total antioxidant status. Relative to the doxorubicin group, exenatide lowered HMGB1 by 48.3%, hepatic 99mTc-pyrophosphate uptake by 48.7%, malondialdehyde by 45.0%, total oxidant status by 37.3%, nitric oxide by 40.7%, NF-κB by 40.4%, TNF-α by 48.6%, and IL-6 by 41.1%, while increasing SIRT1 by 91.7%, IL-10 by 115%, glutathione by 115%, and total antioxidant status by 87.8%. None of the altered parameters returned completely to control levels, indicating attenuation rather than full normalization of acute injury-related changes. Conclusions: Exenatide attenuated doxorubicin-induced acute hepatic injury in this rat model and was associated with reduced oxidative stress, reduced inflammatory activation, higher hepatic SIRT1 levels, lower serum HMGB1 levels, and reduced hepatic 99mTc-pyrophosphate uptake. The findings are consistent with involvement of SIRT1-HMGB1/NF-κB-related signaling, but they do not establish causality. Hepatic 99mTc-pyrophosphate uptake should be interpreted as an exploratory imaging correlate of tissue injury rather than an established liver biomarker. Additional studies incorporating histopathology, immunohistochemistry, functional liver indices, mechanistic validation of SIRT1, and tumor-bearing models are required before translational conclusions can be drawn.
