The S100 protein family is a group of calcium-dependent regulatory proteins widely distributed across various cells and tissues playing roles in numerous physiological and pathological processes. In recent years the involvement of S100 proteins in metabolic diseases especially obesity type 2 diabetes and non - alcoholic fatty liver disease has attracted considerable attention. Research indicates that S100 proteins regulate energy balance and insulin resistance by modulating key cellular signaling pathways including inflammation fat metabolism and insulin signaling. Members such as S100A8 / A9 S100B and S100A4 interact with receptors like receptor for advanced glycation end products and Toll-like receptor-4 activating downstream inflammatory pathways that affect immune responses and metabolic dysregulation. Additionally changes in the expression of S100 proteins in organs like adipose tissue liver and pancreas further exacerbate the progression of metabolic diseases. Despite these insights the specific molecular mechanisms and clinical applications of S100 proteins in metabolic diseases still require further investigation. This review summarizes the research progress on the role of the S100 protein family in metabolic diseases and discusses its potential as a therapeutic target providing theoretical foundations for future diagnostic and treatment strategies.