Professor Jiwoong Choi's research team from the Department of Pharmacology at Gachon University College of Pharmacy has identified S1P4, one of the sphingosine 1-phosphate (S1P) receptors, as a novel pathogenic factor in ischemic stroke, an intractable disease. The team has also proposed a new therapeutic strategy targeting S1P4.

S1P receptors (S1P1-5) regulate various physiological functions and are known to act as key factors in numerous diseases. While previous research has predominantly focused on S1P1, due to the absence of selective modulators for other receptors, particularly S1P4, studies on these receptors have been limited.

Recently, the research team developed a novel S1P4-selective antagonist (NXC736), which has been transferred to NextGen Bioscience and successfully completed Phase 1 clinical trials. The team previously demonstrated the pathological role of S1P4 in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as NASH) in a study published in Cellular and Molecular Gastroenterology and Hepatology in 2022.

In the latest study, the team synthesized NXC736 and investigated its S1P4-selective activity. They discovered that S1P4 acts as a novel pathogenic mechanism in ischemic stroke and that inhibiting S1P4 using NXC736 alleviates brain damage.

Ischemic stroke, accounting for 87% of all strokes, is a condition characterized by blocked cerebral blood flow, leading to neuronal damage and death. Using an animal model of ischemic stroke, the researchers found that S1P4 regulates neuroinflammatory responses, including neuronal apoptosis, disruption of the blood-brain barrier, and activation of microglia. Notably, S1P4 mediated the activation of the NLRP3 inflammasome and related signaling pathways in activated microglia, resulting in brain injury. Furthermore, they demonstrated that inhibiting S1P4 with NXC736 effectively reduces both acute and chronic brain damage associated with ischemic stroke, highlighting its potential as a therapeutic approach.

The study, titled "Blocking S1P4 signaling attenuates brain injury in mice with ischemic stroke", has been accepted for publication in the prestigious Journal of Advanced Research (IF=11.4) in February.

This research was supported by the Mid-Career Researcher Program of the Ministry of Science and ICT and the Gachon University Research Fund (2020).