Exendin-4 as a multi-target therapy for Fetal Inflammatory Response Syndrome-induced brain injury

Fetal Inflammatory Response Syndrome (FIRS) is a leading cause of neonatal brain injury for which no specific treatment currently exists. This review proposes that Exendin-4, a glucagon-like peptide-1 receptor agonist, is a promising “network therapy” due to its multi-target actions against the interconnected pathologies of FIRS. We synthesize evidence that Exendin-4 can concurrently mitigate neuroinflammation, protect oligodendrocytes, stabilize the blood–brain barrier, and attenuate excitotoxicity. Furthermore, we explore emerging mechanisms such as microglial metabolic reprogramming and enhanced mitophagy. Finally, we critically evaluate the translational pathway, highlighting challenges in drug delivery and the therapeutic window, and outline a precision medicine framework for its clinical development. This work positions Exendin-4 as a key candidate for overcoming the therapeutic gap in FIRS-associated neuroprotection.