Mechanisms and therapeutic prospects of short-chain fatty acids in neonatal hypoxic–ischemic encephalopathy via modulation of mitochondrial dysfunction and endoplasmic reticulum stress

Neonatal hypoxic–ischemic encephalopathy (HIE) is a common severe neurological disorder following perinatal asphyxia and a leading cause of neonatal mortality and long-term neurodevelopmental impairments, including cerebral palsy, epilepsy, and cognitive and behavioral deficits. It remains one of the primary causes of death and disability in newborns, imposing a substantial burden on families and society. Although therapeutic hypothermia is currently recognized as an effective intervention, its narrow treatment window, limited patient eligibility, and the persistence of significant sequelae in some affected infants underscore the urgent need for adjunctive therapeutic strategies targeting novel mechanisms. In recent years, short-chain fatty acids (SCFAs), which are metabolites of the gut microbiota, have garnered considerable attention due to their neuroprotective effects via the gut–brain axis. This article systematically reviews the potential mechanisms and therapeutic prospects of SCFAs in neonatal HIE, focusing on their modulation of mitochondrial dysfunction and endoplasmic reticulum stress (ERS).