Anatomy changes, signalling pathways, and clinical treatment after ankle sprain

Ankle sprain (AS), a prevalent sports injury, often progresses to chronic ankle instability (CAI) and post-traumatic arthritis if inadequately treated. Despite known clinical manifestations, the molecular mechanisms driving poor rehabilitation outcomes remain unclear. This review aims to explore the pathological changes in anatomical structure and signalling pathways in AS, as well as the therapeutic strategies associated with these mechanisms.

A comprehensive literature search was conducted in four databases: PubMed, Embase, Web of Science, and OVID MEDICINE, covering the period from January 2000 to August 2025. The search terms included combinations of "ankle sprain," "chronic ankle instability," "signaling pathway," "treatment", and so on. Only articles published in English and containing relevant experimental or clinical evidence were considered. Duplication, irrelevant cases, case reports, and non-original studies were excluded.

This study ultimately included 20 references after screening. In AS, transforming growth factor beta-1 drives fibrosis via Smad-dependent collagen overproduction, exacerbating ligament stiffness; Piezo2 dysfunction impairs mechanosensation, contributing to proprioceptive deficits in CAI; and nuclear factor kappa B-mediated matrix metalloproteinase activation perpetuates inflammation and extracellular matrix degradation. Additionally, dysregulated apoptotic pathways further compromise ligament and cartilage integrity. Pharmacological and non-pharmacological strategies showed partial efficacy, but pathway-targeted therapies require further validation.

Integrating biomechanical and molecular insights can optimize AS management. Future research should explore mechanoimmunomodulatory therapies to break the cycle of instability and degeneration.