Reactive Dicarbonyl Scavenging with 2-Hydroxybenzylamine Improves MASH

<b>Background:</b> Products of lipid peroxidation include a number of reactive lipid aldehydes including reactive dicarbonyl electrophiles (DEs) and contribute to disease processes. DEs play a significant role in the development and progression of metabolic-associated steatotic liver disease (MASLD) by contributing to oxidative stress, inflammation, protein dysfunction, and mitochondrial impairment. Reducing DE stress may be a potential strategy for managing MASLD. We hypothesized that the DE scavenger 2-hydroxybenzylamine (2-HOBA) would reduce liver injury by reducing liver protein adduct formation by DE in mouse models of MASLD. <b>Methods:</b> Protein adducts were measured in human livers by immunohistochemistry and immunoblot. The effects of 2-HOBA were assessed in two different mouse models of MASLD. <b>Results:</b> Isolevuglandin (IsoLG) protein adducts were increased in MASH-staged human livers relative to histologically normal controls. Diet-Induced Animal Model of Nonalcoholic Fatty Liver Disease (DIAMOND) mice treated with 2-HOBA exhibited significantly lower fibrosis scores (* <i>p</i> = 0.012) and reduced liver transaminases (AST, <i>p</i> = 0.03) and ALT, <i>p</i> = 0.012) by over 40%. In STAM (Stelic Animal Model) mice, 2-HOBA improved NAFLD activity scores (<i>p</i> = 0.03, NAS), hyperglycemia, and inflammatory cytokines and reduced serum F2-isoprostanes (IsoPs) by 30%, <i>p</i> = 0.05. These improvements were absent mRNA changes in hepatic antioxidant enzymes (<i>Cat</i>, <i>Gpx1</i>, or <i>Sod2</i>) or ROS-generating proteins (p22PHOX, p47PHOX, NOX4 or COX1). <b>Conclusions</b>: DE scavenging with 2-HOBA may be a promising therapeutic strategy for managing MASLD. While findings are currently limited to male mice, a nutraceutical that reduces liver fibrosis could significantly improve the management of MASH by offering a non-invasive treatment option to potentially slow or reverse liver scarring, delay progression to cirrhosis, and improve patient outcomes, while also providing a potential treatment option for patients who may not be suitable for other interventions like liver transplantation.