Sestrin2 Mitigates Neuronal Ferroptosis Following Subarachnoid Hemorrhage via Orchestration of the AMPK/PGC1α/Nrf2 Signaling Axis.
Zhang Yi, Wan Xichen, Zhang Hongyan, Chen Zhaoyan, Xiao Shining, Wang Wansong, Wang Jun, Zheng Renli, Chen Xiuping, Yang Youqing
Abstract
BACKGROUND: Early brain injury after subarachnoid hemorrhage (SAH) involves oxidative stress and ferroptosis. Sestrin2 (SESN2) regulates redox homeostasis, but its role in SAH-induced ferroptosis remains unclear. METHODS: SAH was induced by internal carotid puncture; HT22 cells were hemin-treated. We assessed neurological deficits, brain edema, BBB integrity, iron levels, mitochondrial ultrastructure, and ferroptosis and signaling proteins by Western blot and immunofluorescence. SESN2 function was probed using knockdown, recombinant human SESN2 (rh-SESN2), and pathway inhibitors. RESULTS: rh-SESN2 improved neurological outcomes, attenuated iron accumulation, and preserved mitochondrial morphology after SAH. In HT22 cells, rh-SESN2 increased viability, decreased ROS and MDA, and partially restored SOD activity. rh-SESN2 upregulated GPX4, SLC7A11, and Nrf2 and its nuclear translocation, whereas SESN2 knockdown exacerbated ferroptosis and reduced these proteins. Mechanistically, SESN2 activated AMPK and upregulated PGC1α, facilitating Nrf2 nuclear translocation and inducing antiferroptotic proteins. Pathway inhibition established an AMPK/PGC1α/Nrf2 hierarchy: AMPK inhibition suppressed PGC1α and Nrf2 activation, PGC1α inhibition reduced Nrf2 translocation, and ML385 abrogated SESN2's protective effects. CONCLUSION: SESN2 activates AMPK, which in turn upregulates PGC1α and promotes Nrf2 nuclear translocation, ultimately inhibiting neuronal ferroptosis after SAH. Targeting this AMPK/PGC1α/Nrf2 axis may provide a novel therapeutic approach for post-SAH neuroprotection.
Key Findings
- Recombinant human SESN2 (rh-SESN2) improved neurological outcomes and reduced iron accumulation after subarachnoid hemorrhage (SAH).
- SESN2 activates AMPK, which upregulates PGC1α and promotes Nrf2 nuclear translocation, leading to increased expression of antiferroptotic proteins such as GPX4 and SLC7A11.
- Inhibition of the AMPK/PGC1α/Nrf2 signaling axis abrogates the protective effects of SESN2 against neuronal ferroptosis.
Clinical Significance
Targeting the SESN2-mediated AMPK/PGC1α/Nrf2 signaling pathway offers a promising therapeutic strategy to inhibit neuronal ferroptosis and improve outcomes after subarachnoid hemorrhage.
Citation
Zhang Yi, Wan Xichen, Zhang Hongyanet al.. Sestrin2 Mitigates Neuronal Ferroptosis Following Subarachnoid Hemorrhage via Orchestration of the AMPK/PGC1α/Nrf2 Signaling Axis. CNS neuroscience & therapeutics. 2026-May.