Sestrin2 Exerts a Novel Protective Effect Against <scp>LPS</scp> ‐Induced Ferroptosis via the Nrf2– <scp>SLC7A11</scp> – <scp>GPX4</scp> Signaling Axis

Uveitis is a leading cause of visual impairment linked to systemic inflammatory diseases. Current corticosteroid treatments are limited by significant long-term side effects. Sestrin 2 (SESN2), a stress-responsive antioxidant protein, is implicated in the regulation of ferroptosis and inflammation. This study investigates SESN2's role in modulating inflammation and ferroptosis in endotoxin-induced uveitis (EIU) models, aiming to develop safer therapeutic alternatives for uveitis management. C57BL/6 mice were subjected to EIU via intravitreal injection of lipopolysaccharide (LPS) with or without SESN2-overexpressing adeno-associated virus (AAV). Clinical evaluations, cytokine profiling, and ferroptosis marker assessments were conducted. Additionally, BV2 microglial cells were genetically modified to overexpress or silence SESN2, followed by analyses of inflammatory cytokine production, oxidative stress, ferroptosis-related pathways, mitochondrial function, and involvement of the Nrf2 signaling pathway. SESN2 expression was significantly reduced in vivo and in vitro following LPS treatment. AAV-mediated SESN2 overexpression suppressed inflammatory responses. Mechanistically, SESN2 inhibited ferroptosis by upregulating ferroptosis-resistant proteins (SLC7A11, GPX4) and reducing lipid peroxidation markers (4-HNE). In vitro, SESN2 overexpression reduced oxidative stress and ferroptosis, while SESN2 knockdown exacerbated these effects. SESN2's protective role was mediated by Nrf2 activation, enhancing antioxidant defenses and ferroptosis inhibition. Inhibition of Nrf2 reversed SESN2's protective effects, underscoring the importance of the p62/Nrf2/GPX4 axis in SESN2-mediated ferroptosis protection. SESN2 plays a crucial role in protecting against inflammation and ferroptosis via the Nrf2 pathway, presenting a promising therapeutic target for uveitis management.