A report on the mechanisms of sweeteners in four musculoskeletal disorders: Insights from network toxicology, molecular docking, and molecular dynamics simulations.

Sweeteners are widely-studied food additives linked to metabolism and obesity, yet their musculoskeletal effects remain largely unknown.To investigate the potential effects of sweeteners on the musculoskeletal system, this study integrated network toxicology, molecular docking, and molecular dynamics simulations to systematically analyze the molecular associations between sweetener exposure and intervertebral disc degeneration, myositis, osteoarthritis, and osteoporosis. The results showed that sweeteners may affect musculoskeletal health by interfering with 35 core targets, which are primarily enriched in inflammatory responses, metabolic disorders, and related signaling pathways. Molecular docking revealed that sweeteners exhibited strong binding potential with these core targets, with mogroside and steviol glycosides showing particularly prominent predicted binding affinities. Molecular dynamics simulations further confirmed the binding stability of FASN, NOS2, and PCSK9 with these two sweeteners. This study provides a computational perspective on the potential disruption of musculoskeletal molecular networks by sweeteners, offering new targets and a theoretical basis for subsequent experimental validation and safety assessment.