Occlusal trauma arising from iatrogenic dental treatments, such as poorly adapted restorations, potentially leads to orofacial inflammation and progression to chronic pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), commonly used in dental clinics, reduce pain and inflammation but increase risks to the gastrointestinal tract. A study by our group showed analgesic and anti-inflammatory efficacy and superior gastric cytoprotection of the hydrogen sulfide (H2S) hybrid donor associated with the NSAID, ketoprofen (ATB-352) compared to ketoprofen. The objectives of this study include: i) developing a model of orofacial inflammatory pain resulting from occlusal trauma in rats ii) employing equimolar doses of ATB-352, 4-HTBZ, and ketoprofen, comparatively evaluate the analgesic, anti-inflammatory, and gastric cytoprotection efficacy no occlusal trauma model; iii) evaluate the participation of the caspase-1/IL-1β axis in the protective mechanism of ATB-352 and, iv) determine the safety and gastric cytoprotection promoted by ATB-352 in human intestinal epithelial cell lines. To standardize occlusal trauma, Wistar rats were used and subjected to the installation of 1mm-thick-polymerizable composite resin crowns on the lower right molars for 1, 3, and 7 days. The installation of crowns promoted orofacial hypernociception and an inflammatory response, in a time-dependent manner, from the 1st day, extending to the 7th day, which is more beneficial for the installation of occlusal trauma. Treatment with ATB-352 (4.6; 15 or 46 mg/kg) and 4-HTBZ (1.5; 7.2; 15.6 mg/kg) impairs orofacial mechanical hypernociception, myeloperoxidase (MPO) activity, concentration of cytokines IL-1β and IL-18 in the masseter muscle and expression of 3-nitrotyrosine (3-NT). Treatment with ketoprofen (3, 10, or 30 mg/kg) only prevents inflammatory disruptions and oxidative stress. Simultaneous treatment with ATB-352 (46 mg/kg) for 7 days caused bone loss and inhibited caspase-1 expression in the trigeminal ganglion caused by occlusal trauma, besides being devoid of gastric mucosa damage. In cell culture of glioma lines C6 (GC6), neuro-2a, BV-2, and AGS, treatment with ATB-352 (0001-5 mM) revealed high rates of cellular predictions, via MTT assay. In GC6 and neuro-2a cell lines, concomitant treatment with ATB-352 (0.01 mM) reversed the increase in caspase-1 expression, induced by stimulation with LPS (400 ng/ml) and ATP (2.5-5 mM) for 6 hours. In neuro-2a cells, caspase-1 inhibition by ATB-352 was followed by increased SOD-1 expression and reduced NLRP3. In cultured intestinal epithelial cells, ketoprofen, in equimolar concentration to ATB-35 and 4-HTBZ, reduced cellular viability in HIEC-6 cells stimulated with IFN-γ and TNF-α, and treatment with 4-HTBZ reversed this effect. In Caco-2/TC7 cell culture, IFN-γ and TNF-α stimulus increased paracellular and trans-epithelial permeability, which was reversed by treatment with 4-HTBZ, while ketoprofen potentiated the damage to the monolayer formed by these cells. In conclusion, the installation of resin cr...