TRIM37 regulates HMGB1 ubiquitination to inhibit ferroptosis in Schwann cells and alleviate peripheral nerve injury

Abstract

Peripheral nerve injury (PNI) is a common neurological disorder. Despite advances in surgical and non-surgical interventions, therapeutic outcomes remain suboptimal, necessitating the identification of novel molecular targets. TRIM37, an E3 ubiquitin ligase, has not been investigated in the context of peripheral nerve injury. To address this gap, we first established a rat sciatic nerve injury model to explore whether PNI is associated with ferroptosis and to characterize TRIM37 expression levels in this context. Using DHE staining, immunofluorescence, and ELISA, we quantified ROS levels, GPX4 expression, and oxidative stress markers. Meanwhile, TRIM37 expression was analyzed via qPCR, Western blot, and immunofluorescence. To clarify the direct role of TRIM37 in ferroptosis, we further performed in vitro experiments using H₂O₂-induced ferroptosis in RSC96 cells. Given that TRIM37 functions as an E3 ubiquitin ligase, we then used co-immunoprecipitation and ubiquitination assays to investigate its potential interaction with HMGB1 and the underlying mechanism. Finally, to validate the in vivo relevance, SFI, von Frey test, and histopathological analyses were used to evaluate the impact of TRIM37 on functional recovery after nerve injury. In summary, PNI significantly induced ferroptosis, which was accompanied by reduced TRIM37 expression. Mechanistically, TRIM37 directly interacted with HMGB1 and promoted its ubiquitination and degradation, thereby inhibiting ferroptosis. TRIM37 overexpression reversed these pathological changes by alleviating ferroptosis, enhancing functional recovery, reducing structural damage, and modulating oxidative stress markers in injured sciatic nerves. Thus, TRIM37 is a potential therapeutic target for improving functional recovery in PNI.