I provide a clinician's perspective into MASH patient selection and treatment, especially in light of the first pharmacological treatment option for MASH having only recently become available to patients.

Nisotirostide is a novel NPY2 receptor agonist designed to enhance the metabolic effects of GLP-1 receptor agonists in type 2 diabetes and obesity. In vitro studies showed selective activation of NPY2 receptor signaling, while in vivo studies demonstrated significant reductions in food intake and body weight in mice. Chronic administration in diet-induced obese mice resulted in dose-dependent weight loss and improved glucose homeostasis. These findings suggest that Nisotirostide has the potential to improve glycemic control and reduce body weight in patients with type 2 diabetes and obesity. Clinical evaluation is ongoing.

Glycerol-3-phosphate acyltransferase 1 (GPAT1) is a mitochondrial outer membrane protein that catalyzes the first step of de novo glycerolipid biosynthesis. Hepatic expression of GPAT1 is linked to liver fat accumulation and the severity of nonalcoholic fatty liver diseases. Structure, function, and in vivo models were explored to understand the role of GPAT1 in mediating disease progression and structure-based drug discovery targeting GPAT1 for the treatment of nonalcoholic fatty liver diseases.

WISP1 is a novel MASH drug target identified through analysis of the transcriptomic data of human cirrhotic livers and validated as a driver for liver fibrosis progression in multiple mouse models. In this study, we aimed to identify human WISP1-blocking antibodies and explore their function in treating human fibrosis diseases like MASH and IPF. We established an elegant in vitro screening assay to identify WISP1 blockers and demonstrated the therapeutic benefit of lead antibodies in attenuating liver fibrosis in mouse models. Additional studies are ongoing to develop anti-WISP therapeutics.

Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic membrane enzyme associated with lipid droplet. It is upregulated in patients with non-alcoholic fatty liver disease. Recently, there have been several reports that predicted loss of function variants in HSD17B13 protecting against the progression of steatosis to non-alcoholic steatohepatitis with fibrosis and hepatocellular carcinoma. We report here: (1) Two distinct series of HSD17B13 inhibitors, (2) Crystal structures of HSD17B13 with inhibitors, (3) Enzymatic activities of WT and protective variants of HSD17B13 and (4) Discovery and characterizations of artificial substrates for in vivo biomarkers

I will present on the development of small molecule agonist versions of peptides that bind G protein-coupled receptors (GPCRs) such as GLP-1R that play a role in obesity.

We describe here the design and development of potent peptide analogs that are completely refractory to hydrolytic enzyme action while retaining full biological activity, potency, and efficacy.  This lecture will describe the fundamental design principles, molecular pharmacology, and in vivo data detailing, fine tuning such activity by simple chemical modification of peptides. Some of the compounds described rival or better those used in the clinic.