...developmental disabilities place a huge burden on families, health systems, and society (estimated lifetime costs per person: ~1 million dollars), emphasizing the urgent need for identifying the causes and mechanisms underlying HIE and improved prevention/treatment strategies to reduce perinatal brain damage (Honeycutt et al., 2004). ...targeting SFKs could provide an additional neuroprotective approach to treating preterm infants. Furthermore, Singh-Mallah et al. used N-acetyl cysteine (NAC), which is an antioxidant and has been previously shown to reduce lipopolysaccharide (LPS)-sensitized HI brain injury (Wang et al., 2007), to further confirm that SIRT6 has protective effects on HIE, which is at least partially associated with the regulation of HMGB1 extracellular release since NAC restores SIRT6 and decreases HMGB1 release in LPS-sensitized neonatal brain following HI injury (Singh-Mallah et al.). ...targeting HMGB1 and its attendant sterile inflammatory responses could represent a novel adjunctive therapeutic approach to treat HIE. Interestingly, sildenafil has been demonstrated to cross the blood-brain barrier and has been shown to exert neuroprotective effects based on the evidence of restoring neuronal development, preventing neuronal cell death, reducing neuro-inflammation via reducing reactive astrogliosis and macrophage/microglial activation, promoting functional recovery and mediating blood-flow redistribution after neonatal HI (Charriaut-Marlangue et al., 2014; Gomez-Vallejo et al., 2016; Moretti et al., 2016; Yazdani et al., 2016, 2021; Engels et al., 2017). ...maternal treatment with sildenafil is anti-oxidative and prevents neuronal death in an animal model of fetal ischemia (Ozdegirmenci et al., 2011).