Oridonin attenuates diclofenac-induced organ damage by suppressing endoplasmic reticulum stress and inflammasome activation

Background: Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) extensively prescribed in clinical practice; its use can be associated with toxic effects on multiple organs. These deleterious effects are associated with a combination of oxidative stress, sterile inflammation, and disrupted epithelial barrier integrity. Oridonin has strong antioxidant and anti-inflammatory characteristics, making it a potential candidate for NSAID-induced organ damage. Objective: Evaluate the protective effects of oridonin against diclofenac-induced liver, kidney and stomach toxicity, while elucidating molecular mechanisms involved in oxidative stress modulation, endoplasmic reticulum (ER) stress suppression, inflammasome inhibition and barrier preservation of epithelial cells. Methods: 30 male Sprague-Dawley rats were divided into five groups: normal control, oridonin control, diclofenac (100 mg/kg, IP), and diclofenac treated with low-dose (10 mg/kg) or high-dose (20 mg/kg) oridonin were the experimental conditions. Renal and hepatic function was assessed by serum and urinary markers. Oxidative stress was assessed by the determination of MDA, GSH, and total antioxidant capacity (TAC) in tissue homogenates. Molecular pathways were studied by ELISA and Western blotting to quantify ER stress markers (IRE1, CHOP, PERK) and the TXNIP/NLRP3/Caspase-1 inflammasome axis. Gastric barrier integrity was confirmed by expression measurement of tight junction proteins (Claudin, ZO-1, Occludin), histopathological, and immunohistochemical markers of NF-κB and IL-1β. Results: Oridonin pretreatment led to the recovery of antioxidant defenses and large decreases in the activation of the TXNIP/NLRP3/Caspase-1 axis, and ER stress signaling. In addition, oridonin maintained the gastric mucosal architecture and the expression of critical tight junction proteins and inhibited NF-κB-induced inflammation. Conclusion: Oridonin ameliorates diclofenac-induced multi-organ toxicity by reducing oxidative stress and ER stress, inhibiting the NLRP3 inflammasome, and preserving epithelial barrier integrity. Thus, oridonin can be considered a suitable drug to ameliorate the unwanted side effects of NSAID treatment.