IGFBP5 knockdown is associated with improved early neurovascular regeneration after sciatic nerve injury

Peripheral nerve injury (PNI) disrupts neurovascular integrity and leads to persistent sensory and motor dysfunction. Insulin-like growth factor binding protein 5 (IGFBP5) regulates insulin-like growth factor bioavailability and has also been implicated in apoptosis, fibrosis, and extracellular matrix remodeling; however, its role in peripheral nerve regeneration remains unclear. This study investigated the temporal expression pattern of IGFBP5 following sciatic nerve injury (SNI) and examined whether its suppression is associated with early neurovascular regenerative responses.

A murine SNI model was established, and IGFBP5 was silenced using perineural delivery of lentiviral short hairpin RNA. Neurovascular remodeling, cellular responses, and stress-related changes were evaluated at 5 days post-injury, and functional recovery was assessed longitudinally up to 12 weeks. We observed that IGFBP5 expression was markedly increased in both proximal and distal nerve segments after injury.

IGFBP5 knockdown was associated with increased endothelial and axonal marker signals, accompanied by enhanced Schwann cell– and macrophage-associated responses and reduced myelin-associated signals. In parallel, reduced oxidative and nitrosative stress and decreased apoptotic markers were detected, together with increased proliferative activity during the early phase of regeneration. In addition, IGFBP5 suppression was associated with increased phosphorylation of PI3K–AKT and ERK signaling pathways.

Functional assessments indicated improved motor recovery and higher sciatic functional index scores compared with controls. Together, these findings suggest that IGFBP5 knockdown is associated with a more favorable early neurovascular microenvironment following peripheral nerve injury. Targeting IGFBP5 may represent a potential strategy to modulate early regenerative processes, although further studies are required to define its mechanistic role and long-term effects.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2021-NR060097 to Ji-Kan Ryu) and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2023-00238513 to Jiyeon Ock). Jiyeon Ock and Woo Jean Kim contributed equally to this work. Department of Urology and National Research Center for Sexual Medicine, Inha University School of Medicine, 7- 206, 3rd ST, Shinheung-Dong, Jung-Gu, Incheon, 22332, Republic of Korea Jiyeon Ock, Yan Huang, Fitri Rahma Fridayana, Guo Nan Yin & Ji-Kan Ryu Department of Anatomy, Kosin University College of Medicine, Busan, 49267, Republic of Korea Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, Incheon, 22332, Republic of Korea Yan Huang, Fitri Rahma Fridayana & Ji-Kan Ryu Department of Anatomy, Inha University School of Medicine, Incheon, Republic of Korea Correspondence to Guo Nan Yin or Ji-Kan Ryu.

The authors declare no competing interests. All animal experiments were conducted in accordance with all relevant animal testing and research ethics regulations and in compliance with the animal protocol approved by the Institutional Animal Care and Use Committee (IACUC) of Inha University (Approval No. This study was performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.