β-Sitosterol targets the gut-brain-clock axis to ameliorate circadian disruption and metabolic dysfunction: A herb-pharmacomicrobiomic perspective.

β-Sitosterol (BS) is a phytosterol that may contribute to circadian and metabolic regulation through multiple predicted mechanisms. Using network pharmacology, gene expression profiling, and microbiome analysis, this study suggests that BS could interact with nuclear receptors (PPARγ, PPARα, RORα, RORγ) and potentially influence CLOCK:BMAL1 transcriptional rhythms in peripheral tissues. BS was also predicted to be associated with PER2-related feedback and the synchronization of gluconeogenic and lipogenic pathways with the light-dark cycle. In addition, computational and preclinical evidence indicates that BS may influence the gut microbiome, supporting short-chain fatty acid-producing bacteria, intestinal barrier integrity, and inflammatory balance. Limited preclinical findings further suggest a potential role for BS in mitigating circadian misalignment and insulin resistance, with possible implications for lipid homeostasis. Future clinical studies are warranted to investigate BS supplementation across different chronotypes and dietary conditions in order to evaluate its chronotherapeutic potential. While the findings are promising, they remain preliminary, and human validation is essential to determine dosing strategies and therapeutic relevance. This study, therefore, highlights BS as a candidate compound with potential relevance to circadian disruptions and metabolic disorders, pending further experimental confirmation.