TRIM59 alleviates neuronal ferroptosis and promotes functional recovery after spinal cord injury by mediating ubiquitination and degradation of ANXA2

Abstract

Background

Spinal cord injury (SCI) is a severe central nervous system disorder for which effective therapeutic interventions remain limited. Accumulating evidence indicates that ferroptosis is a key contributor to secondary neuronal damage following SCI, yet its upstream regulators—particularly those involving post-translational modifications such as ubiquitination—remain incompletely understood. This study aimed to determine whether the E3 ubiquitin ligase TRIM59 modulates neuronal ferroptosis and functional recovery after SCI, and to elucidate its molecular substrate and underlying mechanism of action.

Methods

TRIM59 expression was modulated using lentiviral vectors in cultured neurons and adeno-associated virus serotype 9 (AAV9) in mice. Functional recovery was assessed through the BMS, inclined plane test, footprint analysis, and motor evoked potentials. Ferroptosis was evaluated via biochemical assays, BODIPY C11 staining, ROS detection, TEM, and ferroptosis markers. Molecular interactions were analyzed by co-immunoprecipitation (Co-IP), ubiquitination assays, and cycloheximide (CHX) chase experiment.

Results

TRIM59 expression was significantly downregulated during Erastin-induced ferroptosis in neurons and in spinal cord tissue during the acute phase (days 1–3) after SCI. Downregulation of TRIM59 exacerbated the hallmark features of ferroptosis and impaired motor recovery, whereas TRIM59 overexpression attenuated ferroptosis and promoted neurological restoration. Mechanistically, TRIM59 directly bound to ANXA2 and mediated its K48-linked polyubiquitination and subsequent proteasomal degradation. The neuroprotective effect of TRIM59 was abolished by a catalytically inactive C30A mutant or by ANXA2 overexpression, whereas ANXA2 knockdown rescued the ferroptosis and functional deficits induced by TRIM59 deficiency.

Conclusion

This study identifies a novel TRIM59–ANXA2 regulatory axis that critically governs neuronal ferroptosis and functional recovery after SCI. TRIM59 functions as an endogenous suppressor of ferroptosis by targeting ANXA2 for K48-linked ubiquitin–proteasome–mediated degradation. These findings not only elucidate a key post-translational mechanism in SCI pathophysiology but also position TRIM59 as a promising therapeutic target for neuroprotection and functional restoration following SCI.

The translational potential of this article

Targeting the TRIM59–ANXA2 pathway offers a promising therapeutic strategy to inhibit ferroptosis and promote neuroprotection and functional recovery after SCI. Enhancing TRIM59 activity or disrupting ANXA2 stability could pave the way for novel treatments in clinical neurotrauma.