Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association · 2026
miR-10a-5p Attenuates spinal cord ischemia/reperfusion injury by targeting transforming growth factor beta-activated kinase 1 to suppress Acyl-CoA synthetase long-chain family member 4-mediated ferroptosis in male rats.
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Zhang Dong, Feng Songxin, Tan Zhibin, Zheng Shuang, Luo Lin, Tong Xiangyi, Chen Fengshou
Аннотация
BACKGROUND: Spinal cord ischemia/reperfusion (I/R) injury is a severe complication following thoracoabdominal aortic surgeries, often leading to paraplegia. Ferroptosis, an iron-dependent form of regulated cell death, contributes significantly to this pathology. This study investigates the hypothesis that miR-10a-5p attenuates spinal cord I/R injury by targeting TAK1, thereby suppressing ACSL4-mediated ferroptosis and neuroinflammation.
METHODS: A spinal cord I/R injury model was established in male Sprague-Dawley male rats via transient aortic occlusion. Intrathecal injections of the ferroptosis inhibitor Liproxstatin-1 (Lip-1), siRNA targeting ACSL4 or TAK1, and miR-10a-5p agomir/antagomir were administered prior to ischemia induction. Neurological function was assessed using Tarlov scores. Histopathological changes were evaluated by H&E, Nissl, and immunofluorescence staining. Mitochondrial ultrastructure was examined by transmission electron microscopy (TEM). Expression levels of ferroptosis-related markers (ACSL4, GPX4, COX2, FTH1), inflammatory cytokines (TNF-α, IL-1β), and lipid peroxidation products (MDA, 12-HETE, 15-HETE, LPO) were measured using Western blot, qPCR, and ELISA. The targeting relationship between miR-10a-5p and TAK1 was validated by dual-luciferase reporter assay.
RESULTS: Spinal cord I/R injury induced significant neurological deficits, ferroptosis (evidenced by increased iron, MDA, ACSL4, and COX2; decreased GPX4 and GSH), lipid peroxidation, and inflammation. Lip-1 treatment ameliorated these changes. Knockdown of ACSL4 or TAK1 similarly inhibited ferroptosis, reduced inflammation, and improved motor function. Spinal cord I/R injury induced significant downregulation of miR-10a-5p. It directly targeted TAK1, as confirmed by luciferase assay. Consequently, miR-10a-5p overexpression suppressed TAK1/ACSL4 axis, mitigated lipid peroxidation and ferroptosis, and reduced pro-inflammatory cytokine levels (TNF-α and IL-1β), leading to improved neurological outcomes.
CONCLUSION: This study demonstrates that miR-10a-5p plays a protective role in spinal cord I/R injury by targeting TAK1, thereby suppressing ACSL4-mediated ferroptosis and neuroinflammation. These findings highlight the potential of the miR-10a-5p/TAK1/ACSL4 axis as a novel therapeutic target for preventing and treating spinal cord I/R injury.
METHODS: A spinal cord I/R injury model was established in male Sprague-Dawley male rats via transient aortic occlusion. Intrathecal injections of the ferroptosis inhibitor Liproxstatin-1 (Lip-1), siRNA targeting ACSL4 or TAK1, and miR-10a-5p agomir/antagomir were administered prior to ischemia induction. Neurological function was assessed using Tarlov scores. Histopathological changes were evaluated by H&E, Nissl, and immunofluorescence staining. Mitochondrial ultrastructure was examined by transmission electron microscopy (TEM). Expression levels of ferroptosis-related markers (ACSL4, GPX4, COX2, FTH1), inflammatory cytokines (TNF-α, IL-1β), and lipid peroxidation products (MDA, 12-HETE, 15-HETE, LPO) were measured using Western blot, qPCR, and ELISA. The targeting relationship between miR-10a-5p and TAK1 was validated by dual-luciferase reporter assay.
RESULTS: Spinal cord I/R injury induced significant neurological deficits, ferroptosis (evidenced by increased iron, MDA, ACSL4, and COX2; decreased GPX4 and GSH), lipid peroxidation, and inflammation. Lip-1 treatment ameliorated these changes. Knockdown of ACSL4 or TAK1 similarly inhibited ferroptosis, reduced inflammation, and improved motor function. Spinal cord I/R injury induced significant downregulation of miR-10a-5p. It directly targeted TAK1, as confirmed by luciferase assay. Consequently, miR-10a-5p overexpression suppressed TAK1/ACSL4 axis, mitigated lipid peroxidation and ferroptosis, and reduced pro-inflammatory cytokine levels (TNF-α and IL-1β), leading to improved neurological outcomes.
CONCLUSION: This study demonstrates that miR-10a-5p plays a protective role in spinal cord I/R injury by targeting TAK1, thereby suppressing ACSL4-mediated ferroptosis and neuroinflammation. These findings highlight the potential of the miR-10a-5p/TAK1/ACSL4 axis as a novel therapeutic target for preventing and treating spinal cord I/R injury.