Research progress on spermidine for the amelioration of metabolic diseases

Metabolic disorders comprise a group of diseases characterized by disturbances in energy metabolism, including major public health challenges such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Spermidine, a ubiquitous, naturally occurring polyamine, is essential for maintaining physiological health and sustaining metabolic balance. In the context of ageing research, spermidine has been shown to exert diverse and significant biological effects. Recent findings have increased interest in its capacity to improve metabolic health. Epidemiological evidence indicates a strong inverse association between dietary spermidine intake and the incidence of diabetes and cardiovascular diseases. Notably, spermidine concentrations decline progressively with age, particularly in elderly populations with a high prevalence of metabolic disorders. However, the mechanisms by which spermidine influences metabolic disease, as well as its therapeutic potential, remain incompletely understood. This review aims to systematically examine the biological roles of spermidine in metabolic disorders and elucidate the molecular mechanisms involved, providing a foundation for novel preventive and therapeutic strategies. This review first outlines the biosynthetic and transport pathways of spermidine, establishing a framework for understanding the origins and regulation of its biological functions. In vivo, the mammalian spermidine pool is derived from three primary sources: dietary intake, de novo biosynthesis, and gut microbiota-derived production. Its distribution and regulation rely on coordinated enzymatic cascades and membrane transport systems. The review then summarizes and discusses the key molecular mechanisms underlying spermidine’s putative protective actions, which include: stimulation of autophagy to remove misfolded proteins and damaged organelles; serving as a substrate for eIF5A hypusination, thereby modulating translation and cell proliferation; suppression of pro-inflammatory signaling pathways such as NF-κB to reduce tissue inflammation; inhibition of apoptotic process and reinforcement of antioxidant defense to promote cell survival; and optimization of mitochondrial function to enhance metabolic efficiency. These interconnected processes establish spermidine as a critical regulator of metabolic stability. Through these mechanisms, spermidine demonstrates broad prophylactic and therapeutic potential across a spectrum of metabolic disorders. In obesity, it promotes weight management by activating adipose tissue lipolysis, enhancing thermogenesis in brown adipose tissue, and improving gut microbiota composition and intestinal barrier function. In diabetes, it contributes to glycaemic control by improving peripheral insulin sensitivity, preserving pancreatic β-cell function, and alleviating vascular endothelial inflammatory injury. In MASLD, it mitigates hepatic steatosis and inflammation by enhancing fatty acid oxidation, reducing lipid accumulation, and directly improving mitochondrial function, thereby retarding the progression of fibrosis. In cardiovascular diseases, it confers protection against hypertension and atherosclerosis through multiple pathways, including inducing cardiomyocyte autophagy to improve cardiac function and elasticity, modulating blood lipid profiles, inhibiting platelet aggregation, and stabilizing atherosclerotic plaques. In conclusion, spermidine supports metabolic homeostasis through a multifaceted, synergistic network of molecular actions, offering promising avenues for intervention in multiple metabolic disorders, as evidenced by preclinical research. However, its effects are influenced by cellular context and environmental factors, and translation to clinical practice is challenged by limited human trial data, uncertain dose-response parameters, and potential context-dependent adverse effects. Future advancements will require robust clinical studies informed by a comprehensive understanding of its complex molecular interactions and systems-level biology, with the ultimate goal of defining optimal therapeutic parameters and advancing spermidine as a viable strategy for metabolic disease prevention and treatment.