8480 TIX100, a Novel Small Molecule for the Treatment of MASLD/MASH

Abstract Disclosure: S. Jo: None. J. Chen: None. G. Jing: None. K.M. Habegger: None. A. Shalev: Other; Self; TIXiMED, Inc. Founder & CSO. Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) (aka NAFLD and NASH) affect over 1 billion people worldwide, yet no approved therapy is currently available. MASLD/MASH is often associated with diabetes and obesity and some diabetes medications have shown some beneficial effects in this context. However, beyond steatosis these drugs are in general unable to prevent all the problems associated with MASH, such as inflammation, hepatocyte injury and especially fibrosis. Interestingly, we have now discovered that the new antidiabetic small molecule thioredoxin-interacting protein (TXNIP) inhibitor, TIX100, effectively protects against high-fat diet-induced hepatic steatosis. Oral TIX100 also protected obese and diabetic db/db mice against steatosis and significantly reduced the elevated expression levels of lipogenic genes found in db/db livers, many of which have been shown to be elevated in human MASLD. In addition though, TIX100 also normalized the blood glucose of db/db mice to the levels observed in lean control animals. Therefore, to address the question of whether TIX100 would still be effective in the absence of diabetes, obesity and any genetic leptin-receptor deficiency, we used a validated choline-deficient, amino acid-defined, high-fat diet to induce MASH. Indeed, compared to control chow, this diet significantly increased plasma liver enzymes indicating liver injury without causing diabetes or obesity. It also led to elevated hepatic expression of inflammatory and fibrogenic markers and histology revealed lipid accumulation and steatosis as well as pronounced fibrosis and upregulation of liver macrophages. Excitingly, all these pathological changes were blunted or improved by oral TIX100 treatment. Taken together, oral TIX100 may provide an attractive and effective novel approach for the treatment of MASLD/MASH that goes beyond the correction of diabetes, obesity, and steatosis. Presentation: 6/3/2024