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논문분류	춘계학술대회 초록집
제목	MIT-003 Selectively Protects Hippocampal Neurons from Uremic Toxin-Induced Ferroptosis via the NRF2/GPX4/SLC7A11 Pathway, Independent of Renal Function Recovery, in an Ischemia-Reperfusion Acute Kidney Injury Model
저자	Janghyun Jo
출판정보	2026; 2026(1):
키워드	MIT-003, ferroptosis, indoxyl sulfate, hippocampal neurodegeneration;
초록	Objectives: Renal failure leads to systemic accumulation of uremic toxins, notably indoxyl sulfate (IS), causing hippocampal neuronal injury and cognitive impairment. Ferroptosis—iron-dependent cell death driven by lipid peroxidation and suppression of the NRF2/GPX4/SLC7A11 antioxidant axis—has emerged as a key mechanism of uremic neurotoxicity. MIT-003, a novel synthetic compound, was investigated for its ability to protect hippocampal neurons from uremia-induced ferroptosis independently of renal function. Methods: In vitro: HT-22 hippocampal neurons were exposed to IS (5 mM, 24 h) ± MIT-003 (0.1, 0.5 μM). Cell viability (MTT), cytotoxicity (LDH), intracellular Fe²⁺, lipid peroxidation (MDA), antioxidant capacity (GSH), and GPX4 expression (Western blot) were assessed. In vivo: A renal failure model with sustained uremic toxin elevation was established in mice. MIT-003 was administered systemically. Serum BUN and s-Cr confirmed equivalent uremic burden between groups. Hippocampal tissue was analyzed by immunofluorescence (NeuN, Ki67, TUNEL, DHE) and Western blot (GPX4, NRF2, SLC7A11, xCT). Results: In vitro: IS significantly reduced cell viability and elevated LDH cytotoxicity (p < 0.001). IS induced intracellular Fe²⁺ accumulation (~2.0-fold, p < 0.001), elevated MDA (~1.0 nmol/mg, p < 0.001), depleted GSH (p < 0.01), and suppressed GPX4 (p < 0.001)—consistent with ferroptosis. MIT-003 dose-dependently reversed all these changes (p < 0.05–0.001). In vivo: MIT-003 did not alter BUN, s-Cr, or renal injury scores versus uremic controls, confirming equivalent uremic burden. Nevertheless, MIT-003 significantly restored NeuN⁺ and Ki67⁺ cell counts (p < 0.001, p < 0.05), reduced TUNEL⁺ cells from ~8 to ~1 cell/field (p < 0.001), attenuated DHE oxidative stress (p < 0.05), and recovered hippocampal GPX4, NRF2, SLC7A11, and xCT expression (p < 0.05–0.001). Conclusion: MIT-003 selectively protects hippocampal neurons from uremia-induced ferroptosis by restoring the NRF2/GPX4/SLC7A11 axis. These findings position MIT-003 as a promising therapeutic candidate for uremic encephalopathy across the full spectrum of renal failure.
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