Investigation of organosulfur molecules in experimental acute pancreatitis: Antioxidant and antiferroptotic actions of ATB-346

Aims Acute pancreatitis (AP), an acute inflammatory disorder of the exocrine pancreas, is a potentially life-threatening disease with no specific treatment. Hydrogen sulfide (H 2 S) donor organosulfur compounds administered exogenously typically exert anti-inflammatory effects. We aimed to compare the five most widely studied organosulfurs (ATB-346, dimethyl trisulfide, diallyl trisulfide, GYY4137, AP39) as therapeutic agents against experimental AP in mice, select the most effective one and provide insights into its mechanisms of action. Results Each organosulfur molecule dose-dependently decreased the histological and laboratory markers of inflammation in cerulein-induced AP and demonstrated in vitro cytoprotective effects. ATB-346 was selected for further investigations. It alleviated the severity of ethanol and palmitoleic-acid-induced AP as well, and showed antioxidant properties by upregulating antioxidant enzymes and lowering intracellular reactive oxygen species (ROS) levels. Furthermore, it enhanced the expression of genes involved in ferroptosis defense, reduced malondialdehyde concentration, enhanced glutathione peroxidase 4 (GPX4) expression and protected acinar cells from ferroptosis-inducing treatments. ATB-346 demonstrated greater potency at the same concentration compared to the parent compounds, naproxen or 4-hydroxy-thiobenzamide alone, regarding both antioxidant and anti-ferroptotic effects. Innovation Our findings reveal new insights into the anti-inflammatory effects of organosulfur compounds in AP and demonstrate that ATB-346 - a cyclooxygenase inhibitor with H 2 S-donor properties - reduces inflammation, oxidative stress, and ferroptosis. These effects are mediated through enhancement of the GPX4 antioxidant system, as well as via GPX4-independent mechanisms. Conclusion Our results indicate that ATB-346 possesses anti-inflammatory and cytoprotective properties, thus making it a promising candidate in the treatment of AP.