The exercise-induced irisin–BDNF axis: a systematic review of evidence and translational implications

Abstract

Background: Exercise is a central regulator of metabolic and neurotrophic processes, in which irisin and brain-derived neurotrophic factor (BDNF) play key roles in mediating muscle–brain communication. Objective: This systematic review aimed to summarize the effects of different exercise modalities and immobilization on irisin and BDNF expression, focusing on the PGC-1alpha–FNDC5–irisin signaling pathway. Methods: The review followed the PRISMA 2020 guidelines. Studies published between January 1995 and September 2025 were identified through PubMed, Scopus, Web of Science, and Google Scholar using Boolean search combinations (‘irisin’ AND ‘BDNF’ AND ‘exercise’). Inclusion criteria covered human and animal studies exploring the irisin–BDNF axis. Data were extracted independently and synthesized qualitatively. Risk of bias was assessed using Cochrane domains. Results: Evidence indicates endurance, resistance, and high-intensity interval training increase circulating irisin and hippocampal BDNF levels. Acute exercise induces transient increases, whereas chronic training produces sustained adaptations. Immobilization reduces both irisin and BDNF expression. Conclusions: Current evidence suggests the PGC-1alpha–FNDC5–irisin–BDNF axis may constitute a molecular link between skeletal muscle activity and brain health; causal conclusions are limited by the associative and largely preclinical nature of the evidence. This review was not prospectively registered. Methodological heterogeneity precluded meta-analysis. Data extraction sheets and full search strings are available as supplementary material.