Lcn2 Promotes Ferroptosis in Intracerebral Hemorrhage by Targeting Keap1 Tyr572 and Restricting Nrf2 Activation

Ferroptosis is a major driver of neuronal injury after intracerebral hemorrhage (ICH). Lipocalin‑2 (Lcn2), an iron‑binding transport protein, modulates neuronal iron homeostasis and has been reported to exert both neurotoxic and neuroprotective actions. The precise contribution of Lcn2 to ferroptosis following ICH remains unresolved. Here, it is found that Lcn2 concentrations were significantly higher in hematoma than in arterial blood from the same patients. Proteomics and inflammation‑array data converged on ferroptosis and the Nrf2-Keap1 axis as key pathways altered in Lcn2^fl/flNestin^Cre mice. Lcn2 deletion improved mitochondrial integrity and reduced lipid peroxidation in primary neurons. Mechanistically, Lcn2 competitively bound Keap1 at Tyr572, restricting Nrf2 nuclear translocation and thereby promoting ferroptosis. Knockdown of Nrf2 or pharmacological inhibition with HY‑149508 (Nrf2 inhibitor) abrogated the Lcn2‑knockout-mediated rescue of neuronal activity and mitochondrial function. Notably, treatment with a Keap1 Tyr572Ala mutant by adeno-associated viruses conferred robust neuroprotection only in the presence of Lcn2. Lcn2 promotes ferroptosis neuronal death after ICH by engaging Keap1 at Tyr572 to suppress Nrf2 activation. The therapeutic efficacy of Keap1(Tyr572Ala) is contingent on Lcn2 expression, revealing an unexpected context dependence within the Lcn2-Nrf2 signaling axis. These findings identify a tractable molecular interface for precision modulation of ferroptosis in ICH.