Comparative network pharmacology of artificial sweeteners to understand Its health consequences

Background Artificial sweeteners (ASwt) are widely consumed sugar substitutes, but their long-term health effects remain a subject of debate. While regulatory bodies generally consider them safe at recommended doses, concerns persist regarding potential adverse effects. This study aimed to investigate the interactions between ASwt and biological targets using in silico analysis, focusing on target affinity, selectivity, and tissue expression. Methods Five common ASwt – acesulfame K (Ac), aspartame (As), sucralose (Su), steviol (St), and saccharin (Sa) were evaluated. Their target interactions were predicted using a cheminformatics approach, analysing affinity towards functional groups and protein targets. Concentration/affinity (C/A) ratios were calculated to assess the likelihood of target activation at achievable doses. Expression of high-affinity targets with significant C/A ratios in various organs was assessed using the Human Protein Atlas database. Results : The ASwt displayed potential to modulate most of the functional groups at physiologically feasible affinities. Ac exhibited a broad range of targets, while St showed a preference for kinases and proteases. Notably, As and Su demonstrated interactions with membrane receptors and kinases. C/A ratio analysis revealed potential concerns for As and Su. Several of its targets, including ROCK2, ACE, ITGA2/5, PIM2, KDM5C, PIM1, SLC1A2, SETD2, CAPN1, LTA4H, MKNK2, HDAC1 and CDK, showed high C/A ratios, suggesting possible functional modulation at achievable intake levels. Organ specific expression analysis identified the endocrine, respiratory, renal, reproductive, central nervous, digestive, and musculoskeletal systems as a region particularly susceptible due to the high expression of high affinity targets linked to cell growth, extracellular matrix, epigenetic regulations, and inflammation. Interestingly, 30 tissues expressed high-affinity targets for both As and Su, while 14 tissues exclusively expressed targets for As. Conclusion : This study highlights the potential for ASwt to interact with various biological targets, particularly As and Su. The high C/A ratios of some As targets and the tissue-specific expression patterns suggest potential safety concerns that require in vivo validation. ### Competing Interest Statement The authors have declared no competing interest.