The Dual Regulatory Role of the ERK Signaling Pathway in Peripheral Nerve Injury Repair: From Mechanistic Analysis to Targeted Intervention

Abstract

ABSTRACT Peripheral nerve injury (PNI) is a common traumatic neurological condition characterized by high rates of disability and poor functional recovery, posing a major global public health and clinical challenge. Currently, clinical practice has established a comprehensive intervention system centered on microsurgical suturing and autologous nerve grafting as core surgical approaches, supplemented by pharmacological treatments such as methylcobalamin, B‐complex vitamins, and neurotrophic factors. However, existing treatments can only repair neuroanatomical structures and provide symptomatic support; they struggle to fully restore neural function. Furthermore, there is a lack of effective intervention strategies for chronic neuropathy and neuropathic pain, creating an urgent need to identify multi‐target intervention strategies capable of regulating the pathological progression of PNI throughout its entire course. ERK is a core member of the MAPK family, and the Ras/Raf/MEK/ERK signaling cascade it mediates serves as a key hub linking extracellular stimuli to intracellular biological effects. Existing research has confirmed that the ERK signaling pathway is involved in regulating core pathophysiological processes following PNI, including Schwann cell phenotypic transformation, axonal regeneration, neuroinflammatory homeostasis, oxidative stress damage, autophagy regulation, and angiogenesis. This review systematically elucidates the biological basis of the ERK signaling pathway, focuses on its multidimensional and multicellular regulatory mechanisms in PNI repair, and comprehensively summarizes the latest research advances in various intervention strategies targeting the ERK pathway, including small‐molecule drugs, natural bioactive compounds, tissue engineering, and physical therapies.