Neonatal Hypoxic-Ischemic Encephalopathy: From the Limitations of Therapeutic Hypothermia to Precision Intervention.

Therapeutic hypothermia (TH) is the current standard of care for moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE). However, its clinical application faces significant limitations, including a 44-55% rate of death or disability, a narrow 6‑h therapeutic window, inequitable global access, and inconsistent patient selection. These challenges highlight the need for emerging strategies that may complement or integrated with TH in the future. This review systematically synthesizes emerging therapeutic strategies beyond TH, encompassing four cutting-edge directions: first, targeting mitochondrial dysfunction and metabolic reprogramming; second, modulating neuroinflammation and immune responses; third, inhibiting programmed cell death pathways; and fourth, promoting neural repair and regeneration. We also discuss combination regimens, including sildenafil, resveratrol, and melatonin with magnesium, which have shown promise in preclinical or early clinical studies, while acknowledging that erythropoietin failed to show added benefit in Phase III trials. Importantly, most of the novel interventions discussed remain at preclinical or early‑phase clinical stages. To facilitate future translation, we systematically delineate the critical support infrastructure for HIE management in the precision medicine era: multimodal biomarkers and risk stratification, including neuroimaging, neuroelectrophysiology, fluid biomarkers, and clinical risk scoring models. By integrating these tools, it will be possible to rapidly identify the dominant injury pathway in each infant within the "golden 6-hour" window, implement individualized combination interventions, and promptly deploy neurorestorative strategies during the subacute phase. Realizing this vision will require global collaboration, standardized data sharing, and low-cost interventions tailored for LMICs. In conclusion, while precision medicine holds great promise for HIE, it is not yet an established replacement for therapeutic hypothermia; rather, it represents a scientifically rational and evolving strategy that requires rigorous clinical validation to improve long‑term outcomes for affected neonates.