Fasudil Protects Against Diclofenac-Induced Hepatorenal and Gastric Injury via Modulation of ROCK/TLR4/SIRT1 Signaling and Preservation of Tight Junctions.

Diclofenac is a widely consumed non-steroidal anti-inflammatory drug, yet its clinical utility is limited by severe hepatotoxicity, acute kidney injury, and gastric ulceration. While the RhoA/ROCK pathway is implicated in inflammation, its potential as a therapeutic target for multi-organ NSAID toxicity remains unexplored. This study evaluated the dose-dependent protective effects of the ROCK inhibitor, fasudil, against diclofenac-induced damage and investigated the underlying ROCK2/TLR4/SIRT1 axis. Five separate cohorts were established using thirty male Sprague-Dawley rats. Alongside a normal control and fasudil control group, one experimental group was treated with 100 mg/kg diclofenac. Furthermore, two distinct groups were pretreated with fasudil for seven days before induction, receiving either a 10 mg/kg or a 30 mg/kg dose prior to diclofenac administration. Diclofenac provoked severe hepatic, renal, and gastric injury accompanied by marked oxidative stress. Pretreatment with fasudil markedly reversed these effects and improved hepatic and renal function biomarkers. Mechanistically, fasudil reduced renal and hepatic ROCK2 and TLR4 expression, which consequently suppressed downstream systemic inflammatory markers, including NF-κB and TNF-α. Furthermore, fasudil halted apoptosis by restoring SIRT1 expression and reducing cleaved caspase-3, alongside preserving gastric barrier integrity. Fasudil dose-dependently ameliorates diclofenac-induced hepatic, renal, and gastric injury by silencing the ROCK2/TLR4 inflammatory axis, restoring SIRT1 survival networks, and protecting epithelial tight junctions.