Hepatic Effects of Etoricoxib in Mice: Integrated Histopathological and Gene Expression Analysis

<b>Background</b>: Etoricoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is widely prescribed for the management of inflammatory conditions. Despite its extensive clinical use, evidence regarding its hepatic safety profile remains limited and incompletely characterized. <b>Aims</b>: This study aimed to systematically evaluate the hepatic effects of etoricoxib in a murine model by integrating histopathological assessment with analysis of mRNA expression of key enzymes involved in arachidonic acid metabolism <b>Methods</b>: Male BALB/c mice (<i>n</i> = 7 per group) received either low or high doses of etoricoxib (10.5 or 21 mg/kg/day) or celecoxib (35 or 70 mg/kg/day) for 28 consecutive days. Liver tissues were examined histologically using hematoxylin and eosin staining, while molecular alterations were assessed by quantitative PCR targeting representative cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) isoforms involved in arachidonic acid metabolism. <b>Results</b>: High-dose etoricoxib exposure was associated with pronounced hepatic histopathological alterations, including hepatocellular necrosis, inflammatory cell infiltration, and sinusoidal congestion. In contrast, low-dose treatment resulted in only mild vascular and cellular changes. At the molecular level, etoricoxib administration was associated with marked downregulation of several arachidonic acid-metabolizing genes (including <i>Cyp4a12</i> and <i>Alox12</i>), whereas <i>Cox2</i> expression was significantly upregulated (<i>p</i> < 0.05), indicating a shift toward a pro-inflammatory transcriptional profile. <b>Conclusions</b>: Etoricoxib exposure is associated with dose-dependent hepatic injury in mice, accompanied by coordinated transcriptional alterations in arachidonic acid-metabolizing pathways. Notably, molecular changes were detectable even at low doses in the absence of overt histological damage, suggesting potential early indicators of hepatic stress. These findings underscore the importance of cautious dose optimization and further translational studies to clarify the long-term hepatic safety of etoricoxib in clinical settings.