Pleckstrin and Sec7 domain-containing protein 3 (PSD3) (PSD3)

Pleckstrin and Sec7 domain-containing protein 3 (PSD3) is a guanine nucleotide exchange factor (GEF) that facilitates the activation of ARF6, a small GTPase involved in vesicular trafficking and actin remodeling (UniProt Q9NYI0). Recent genomic research has identified PSD3 as a key regulator of hepatic lipid metabolism, with loss-of-function mutations in humans correlating with lower liver fat and a reduced risk of metabolic dysfunction-associated steatohepatitis (MASH) (PMID: 35613349). Consequently, PSD3 mRNA has become a primary target for RNA-targeted therapies, specifically antisense oligonucleotides (ASOs) designed to induce its degradation. The lead candidate in this space, ION449 (also known as AZD2693), is being developed to treat MASH by reducing PSD3 protein levels in the liver, thereby mimicking the protective effect of natural genetic variants (ClinicalTrials.gov NCT04862260). This approach aims to decrease hepatic steatosis and prevent the progression of liver fibrosis and inflammation. Beyond metabolic disease, PSD3 has been implicated in cancer progression due to its role in ARF6-mediated cell signaling and motility (UniProt Q9NYI0). The therapeutic strategy focuses on liver-specific delivery to minimize potential systemic side effects associated with ARF6 inhibition in other tissues.

Other names

EFA6RHCA67Exchange factor for ARF6-relatedPleckstrin and Sec7 domain-containing protein 3

Antisense oligonucleotide-mediated degradation of PSD3 mRNA leading to reduced protein expression and decreased hepatic lipid accumulation.