Herbal bioactive compounds modulating ferroptosis and pyroptosis in neonatal hypoxic-ischemic brain injury: a systematic review of molecular basis, proposed crosstalk, and translational challenges

Background Neonatal hypoxic-ischemic brain injury (HIBI) remains a major cause of neonatal mortality and disability despite therapeutic hypothermia. Ferroptosis and pyroptosis are implicated in HIBI. Purpose To critically evaluate herbal bioactive compounds modulating ferroptosis- and pyroptosis-associated injury in neonatal HIBI. Study design Systematic review conducted and reported following PRISMA 2020. Methods PubMed, Web of Science, and Scopus were searched through September 2026. Eligible studies used in vivo neonatal HIBI models, tested chemically defined plant-derived compounds, reported ferroptosis-related markers or evidence of pyroptotic execution beyond inflammasome activation, and assessed neuroprotective outcomes. Risk of bias was assessed using SYRCLE. Results Of 1,441 records, 17 studies investigating 16 compounds met eligibility criteria. Nine examined ferroptosis and eight examined pyroptosis; glycyrrhizin was the only compound studied across both pathways, in separate studies. Included compounds spanned diverse structural classes and botanical sources. Studies reported reduced pathway-associated markers and improved brain-injury outcomes, but in vivo pathway dependency was demonstrated for only four compounds. No included study reported both ferroptosis-specific and pyroptosis-specific markers in the same neonatal HIBI model. Several risk-of-bias domains were predominantly rated unclear. Conclusion Preclinical studies suggest that herbal bioactives can modulate ferroptosis- and pyroptosis-associated processes in neonatal HIBI and warrant further evaluation as multi-target candidates. However, no study tested whether a single compound modulates both pathways within the same model. Future studies should apply pathway-specific manipulation alongside assessment of the second pathway in the same model and address developmental-stage specificity, therapeutic timing, model variability, brain availability, formulation barriers, and other pharmacological considerations.