Inhibiting ARRB2 for MASH and MASLD

Inhibiting the adaptor protein ARRB2 — which promotes ubiquitination and degradation of the enzyme ACOD1, inhibiting its production of the macrophage regulating-metabolite itaconate — could help treat MASH (formerly known as NASH) and metabolic dysfunction-associated steatotic liver disease (MASLD) by preventing M1 polarization of macrophages, thus decreasing proinflammatory cytokine secretion that promotes lipid accumulation in hepatocytes.

ARRB2 mRNA expression was higher in circulating monocytes from MASLD patients than from individuals without MASLD, and higher monocyte ARRB2 expression was associated with liver injury, steatosis, and higher numbers of circulating innate immune cells. ARRB2 protein expression was higher in liver macrophages from MASH patients and from mice fed a high-fat, high-fat high-cholesterol, or methionine choline-deficient diet than from individuals without MASH and mice fed a normal diet, respectively. ...