Plant-Derived Natural Compounds and Nrf2-Centered Redox Signaling in Intracerebral Hemorrhage: Evidence Grading, Mechanistic Boundaries, and Translational Challenges

Intracerebral hemorrhage (ICH) is a devastating stroke subtype in which secondary brain injury is driven by oxidative stress, iron overload, ferroptosis, neuroinflammation, blood–brain barrier disruption, and defective hematoma clearance. Nrf2 is a redox-sensitive transcription factor that coordinates antioxidant defense, iron handling, inflammatory regulation, and neurovascular unit protection through downstream effectors such as HO-1, NQO1, GPX4, and SLC7A11. Plant-derived natural compounds have been widely investigated in experimental ICH models; however, increased Nrf2 expression or nuclear translocation alone does not establish Nrf2-dependent neuroprotection. Here, we critically appraise preclinical evidence linking plant-derived natural compounds to Nrf2-centered signaling in ICH and classify the evidence into three levels: causal Nrf2-dependent evidence, Nrf2-associated evidence, and indirect or context-transferred evidence. Representative flavonoids, phenolics, terpenoids, lignans, steroidal lactones, and other bioactive compounds are evaluated with attention to ICH-model relevance, causal pathway validation, pharmacokinetic limitations, brain exposure, and therapeutic window. Current evidence indicates that only a limited subset of compounds has been validated by genetic or pharmacological Nrf2 inhibition, whereas most remain supported by pathway association rather than causality, and preclinical studies rely predominantly on young healthy rodent models with early post-ICH intervention. Notably, no compound currently reaches relatively high translational priority because perihematomal brain exposure, delayed-treatment efficacy, and long-term safety evidence remain largely unavailable. We therefore propose an evidence-based prioritization framework integrating Nrf2 causality, ICH-specific efficacy, brain bioavailability, and translational readiness. This review clarifies the mechanistic boundaries of Nrf2-targeted natural compounds and outlines priorities for rigorous translational research in ICH.