Ferroptosis in neonatal and paediatric disease: From molecular mechanism to therapeutic target.

Abstract

Ferroptosis is an iron-dependent regulatory cell death mechanism mediated by lipid peroxidation. Increasing evidence suggests that this process is closely related to the etiology of a variety of paediatric diseases. This review systematically elaborates the core molecular mechanism of ferroptosis, and highlights that newborns exhibit organ‑specific susceptibility to ferroptosis, predominantly attributed to the convergence of high PUFA content in the developing brain and erythrocytes, immature antioxidant defences, and a propensity for free iron accumulation. Building on this, we further examine the role of ferroptosis in multiple childhood disorders, such as bronchopulmonary dysplasia, hypoxic-ischaemic encephalopathy, haemolytic hyperbilirubinemia, necrotizing enterocolitis, retinopathy of prematurity, and neonatal rotavirus‑associated biliary atresia. Furthermore, we synthesize existing evidence, which is largely preclinical, regarding therapeutic interventions that modulate ferroptosis, including iron chelators, selective inhibitors (e.g., ferrostatin-1), and activators of endogenous antioxidant pathways (e.g., Nrf2 inducers). We also discuss the multiple difficulties and challenges encountered by the current study in paediatric clinical trials, especially with respect to ferroptosis‑related issues. This review identifies a series of key barriers to clinical translational research in paediatric ferroptosis, based on a systematic review of the available evidence. In response to these obstacles, we propose a prioritized translational framework that focuses on juvenile animal models, age-stratified pharmacokinetics, and patient-derived organoids, to provide guidance for translating clinical practice to this vulnerable population.