An in silico investigation of hesperidin as a modulator of the irisin/AMPK axis: Implications for exercise-mimetic signaling

Exercise-induced metabolic adaptations are orchestrated by energy-sensing signaling networks centered on 5′-AMP-activated protein kinase (AMPK). Dietary polyphenols, including the citrus flavanone glycoside hesperidin, have been proposed to influence pathways overlapping with those activated during physical activity. However, atomic-level structural evidence describing how hesperidin may interact with AMPK and how such interactions could be positioned within the irisin–AMPK axis remains limited. The aim of the present study was therefore to investigate potential interactions between hesperidin and the catalytic α1 subunit of human AMPK (PRKAA1) using an integrated in silico approach and to evaluate the resulting structural insights within a mechanistic framework capable of guiding future experimental research on exercise-mimetic signaling. An integrated in silico workflow was applied to investigate interactions between hesperidin and the catalytic α1 subunit of human AMPK (PRKAA1). Molecular docking was used to predict binding orientations and energetics within defined binding pockets, followed by binding-site characterization and interaction profiling. The predicted complexes were evaluated in the context of signaling pathways associated with the irisin–AMPK axis to generate mechanistically grounded hypotheses for subsequent experimental validation. Hesperidin adopted structurally compatible binding poses within AMPKα1 and formed extensive interaction networks involving residues located in druggable regions of the protein. Docking scores suggested energetically favorable ligand accommodation, supporting the plausibility of a direct molecular interface between hesperidin and a central metabolic regulator. These findings provide atomic-level insight into how citrus-derived flavanones might engage energy-sensing pathways relevant to exercise physiology. The present in silico analyses identify a structurally coherent interaction between hesperidin and human AMPKα1 and situate this interaction within metabolic signaling frameworks linked to exercise adaptation. Rather than establishing biological efficacy, the results furnish a mechanistic platform for prioritizing future experimental studies, including cellular validation of AMPK activation and well-controlled human intervention trials examining performance, metabolic biomarkers, and supplementation timing.