A New Perspective on Signaling Pathways and Structure–Activity Relationships of Natural Active Ingredients in Metabolic Crosstalk Between Liver and Brown Adipose Tissue: A Narrative Review

ABSTRACT Obesity has become a major global health problem, and strategies to improve metabolic disorders are urgently needed. This review focused on the roles of natural active ingredients in regulating metabolic communication between the liver and brown adipose tissue (BAT), especially highlighting the associated signaling pathways and structure–activity relationship (SAR). Natural polyphenols, flavonoids, terpenoids, and their potential in modulating metabolism were elaborated. Particularly, some signaling factor pathways including insulin, adiponectin, leptin, NRG4, FGF21, inflammatory factor, and BMP were summarized, detailing how natural active ingredients modulated the liver–BAT metabolic crosstalk, such as celastrol, genistein, sesamin, etc. FGF21 and NRG4 acted as key signaling factors, playing important transduction roles in the metabolic crosstalk between the liver and BAT. More importantly, SAR of flavonoids, phenolic acids, polysaccharides, and terpenoid compounds was discussed. The presence of functional groups, hydroxyl or methoxyl substituents, and molecular size were analyzed in relation to the interaction between compounds and biological targets. Furthermore, how structural modifications enhanced bioactivity and bioavailability while reducing side effects was elucidated. In conclusion, natural active ingredients played an important role in modulating metabolic crosstalk between the liver and BAT, underscoring the potential of these components in treating metabolic disorders. Further research on SAR of different natural active ingredients and their long‐term health impacts are still needed to provide more effective and safer natural solutions for metabolic diseases prevention and treatment.