Obeticholic Acid and Methyl Ferulic Acid Mitigate Arsenic Trioxide‐Induced Hepatotoxicity by Targeting Profibrotic and Proinflammatory Signaling

Arsenic, a toxic environmental metalloid, induces liver damage by activating oxidative stress, inflammation, and apoptosis. This study examined the potential ameliorative effects of obeticholic acid (OCA) and methyl ferulic acid (MFA) against arsenic trioxide (ATO)-induced hepatic injury in rats, focusing on the pro-fibrotic TGF-β/Smad3 and pro-inflammatory MAPK pathways. Male Wistar rats received ATO orally at 7.5 mg/kg/day from day 7 to day 21. Concurrently, OCA and MFA were received orally for 21 days, either alone or in combination, at doses of 10 and 100 mg/kg, respectively. The current findings revealed that ATO caused significant hepatic damage, as indicated by derangements in liver function tests and histological damage. Hepatotoxicity was marked by increased oxidative stress markers (NADPH oxidase 1, malondialdehyde, and nitric oxide), lowered antioxidant defenses (GSH, SOD), and elevated pro-inflammatory signals (IL-1β, IL-6, TNF-α, and COX-2). ATO also activated the hepatic profibrotic (TGF-β/Smad3) and pro-inflammatory MAPK cascades and suppressed the anti-apoptotic protein Bcl-2. Treatment with OCA and/or MFA significantly improved liver function and histopathology, restored antioxidant capacity, and decreased oxidative and inflammatory markers. They also inhibited activation of the pro-fibrotic and pro-inflammatory pathways and suppressed apoptosis. The combination of OCA and MFA exhibited the most pronounced hepatoprotective effects. In conclusion, OCA and MFA mitigate ATO-induced hepatotoxicity through their antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. Hence, these findings may pave the way for clinical investigation into their potential use as adjunct therapeutic agents in arsenic-induced hepatotoxicity.