Advances in ERK Signaling Pathway in Traumatic Brain Injury: Mechanisms and Therapeutic Potential

Abstract

Traumatic brain injury (TBI) stands as one of the leading global causes of disability and mortality. Its pathological progression involves intricate secondary injury mechanisms, including oxidative stress, neuroinflammation, apoptosis, and ferroptosis. Current clinical treatments primarily focus on symptom management, yet lack effective intervention strategies targeting core pathological pathways. Recent studies have revealed that the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway plays a pivotal regulatory role in TBI-related secondary injuries. On one hand, the spatiotemporal-specific activation of ERK1/2 exerts neuroprotective effects by modulating neuronal survival, vascular repair, and glial cell phenotypic transformation. Conversely, its hyperactivation exacerbates oxidative damage, inflammatory cascades, and programmed cell death. This review systematically examines the dual roles and molecular mechanisms of the ERK1/2 pathway across distinct pathological processes post-TBI (e.g., apoptosis, autophagy, ferroptosis), while summarizing the neuroprotective efficacy of ERK-targeting pharmacological agents (e.g., tetrahydrocurcumin, ulinastatin) in animal models. These advancements, achieved through precise modulation of ERK pathway activity and functionality, offer novel directions for pathological intervention in TBI.

Keywords: Apoptosis; ERK signaling pathway; ERK1/2; Ferroptosis; Neuroinflammation; Oxidative stress; Traumatic brain injury (TBI).