ArticleCell death and differentiation2025
Redox regulation of TRIM28 facilitates neuronal ferroptosis by promoting SUMOylation and inhibiting OPTN-selective autophagic degradation of ACSL4.
Article in Cell death and differentiation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Emerging regenerative strategies for spinal cord injury: exosome-derived mechanisms and therapeutic insights.Frontiers in neuroscience · 2025Pooled it
- Breaking the cycle of fibrosis: Ferroptosis as a therapeutic target (Review).International journal of molecular medicine · 2026Review
- Ferroptosis-Pyroptosis Crosstalk in Spinal Cord Injury: Molecular Mechanisms, Emerging Connectors, and Staged Therapeutic Perspectives.Journal of molecular neuroscience : MN · 2026Review
- TRIM28 SUMOylates IRF3 in astrocytes to drive neutrophils infiltration and ischemic cerebral injury.Cell death and differentiation · 2026Article
- Subcellular regulation of ferroptosis: roles of individual intracellular organelles and cross talk.American journal of physiology. Cell physiology · 2026Review
- ACSL4 in Alzheimer's disease: Pathogenetic mechanisms and potential therapeutic targets.Genes & diseases · 2026Review
- Diselenide-bridged mesoporous silica nanoplatform for baicalin delivery facilitates spinal cord injury repair via CHCHD2-mediated mitochondrial homeostasis restoration.Materials today. Bio · 2026Article
- TIF1 Family Proteins as Modulators of Cell Death: Mechanisms and Therapeutic Opportunities.Biomolecules · 2026Review
- Nuciferine inhibits pressure overload-induced cardiac remodeling by activating the SENP1-ACSL4-ferroptosis axis.Journal of advanced research · 2026Article
- TRIM28 Is an E3 Ligase of IRP2 Suppressing Ischemia/Reperfusion-Induced Myocardial Ferroptosis.Circulation · 2026Article
- Identification of small ubiquitin-related modifier (SUMO)-related genes-based biomarkers in Alzheimer's disease based on bioinformatics analysis.Scientific reports · 2026Article
- TRIM28 orchestrates SUMO-ubiquitin crosstalk to stabilize PPARG and drive bladder cancer progression.Cell death & disease · 2026Article
- Organelle regulation of SUMOylation: regulatory mechanisms and therapeutic application.Journal of advanced research · 2026Review
- Acyl-CoA Synthetase Long-Chain Family Member 4 in Liver Injury: Multidimensional Regulation and Therapeutic Potential.Gastroenterology research · 2026Review
- CREB5 Inhibits Neuronal Ferroptosis via Transactivating ApoL6 to Regulate Lipid Droplet Metabolism After Spinal Cord Injury.CNS neuroscience & therapeutics · 2026Article
- Solasonine inhibits NSCLC malignant progression by regulating SLC7A11 ubiquitination degradation and inducing ferroptosis.Respiratory research · 2026Article
- LXRα/SCD1-Mediated Endoplasmic Reticulum-Mitochondria Crosstalk in Inhibiting Neuronal Ferroptosis after Spinal Cord Injury.Research (Washington, D.C.) · 2026Article
- ZDHHC2-Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- NEDD4 promotes reactive astrogliosis by enhancing K63-linked ubiquitination and inhibiting chaperone-mediated autophagy degradation of YAP1.International journal of biological sciences · 2026Article
- Post-translational modifications in ferroptosis: mechanisms and therapeutic potential.International journal of biological sciences · 2026Review
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Authors and funding
13 authors.
Funding
Abstract
Ferroptosis is one of the cell death programs occurring after spinal cord injury (SCI) and is driven by iron-dependent phospholipid peroxidation. However, little is known about its underlying regulation mechanism. The present study demonstrated that lipid peroxidation was promoted in patients with SCI. Neurons affected by ferroptosis following SCI had a high expression of ferroptotic protein ACSL4. The E3 SUMOylase TRIM28 promoted neuronal ferroptosis by enhancing ACSL4 expression. Genetic deletion of Trim28 significantly attenuated neuronal ferroptosis and improved mouse hindlimb motor function following SCI. In contrast, mice with Trim28 overexpression demonstrated poor neurological function after SCI, which was attenuated by ferroptosis inhibitor Liproxstatin-1. Mechanistically, TRIM28 bound to ACSL4, promoted SUMO3 modification at lysine (K) 532, and inhibited K63-linked ACSL4 ubiquitination, thereby suppressing OPTN-dependent autophagic degradation. Additionally, SENP3 was identified as the deSUMOylation enzyme that can reverse this process and compete with TRIM28, which was transcriptionally upregulated due to excessive oxidative stress. These data unveiled a mechanism by which TRIM28-mediated SUMOylation regulated neuronal ACSL4 levels and ferroptosis, identified interactions and correlations involved in ACSL4 SUMOylation, ubiquitination, and autophagic degradation, and discovered a positive feedback loop where oxidative stress transcriptionally upregulated Trim28, and conversely TRIM28 promoted ferroptosis and oxidative stress. Notably, screening of the FDA-approved drug library revealed that pharmacological TRIM28/ACSL4 axis interventions with Rutin hydrate inhibited neuronal ferroptosis and improved hindlimb motor function in mice after SCI, thus providing a promising therapeutic strategy for its treatment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.