Sphingolipid metabolism meets natural bioactives: A new perspective on metabolic disease intervention

Dysregulation of sphingolipid metabolism, particularly ceramide accumulation, has emerged as a central pathogenic driver of metabolic diseases including obesity, type 2 diabetes, metabolic dysfunction associated steatotic liver disease, and cardiovascular disease. Pharmacological targeting of sphingolipid homeostasis represents a promising therapeutic strategy. Although synthetic inhibitors can achieve selective modulation of specific sphingolipid-related enzymes, their long-term therapeutic application may still be limited by issues such as compensatory metabolic responses, tissue-dependent efficacy, and safety concerns. In this context, natural bioactive compounds derived from dietary and medicinal sources have attracted increasing attention because of their broad regulatory activities across interconnected metabolic and inflammatory pathways. This review summarizes recent advances in how polyphenols, polysaccharides, alkaloids, saponins, and organosulfur compounds regulate ceramide biosynthesis, catabolism, and sphingolipid signaling networks. Mechanistically, these compounds suppress key enzymes involved in de novo ceramide synthesis, including serine palmitoyltransferase, ceramide synthases, and dihydroceramide desaturase, while also promoting ceramide turnover through sphingomyelinases and ceramidases. In addition, emerging lipidomic evidence demonstrates that natural bioactives reprogram pathogenic sphingolipid profiles and improve systemic metabolic homeostasis via the gut microbiota-bile acid-FXR-ceramide axis. We further highlight the emerging role of gut-derived bacterial sphingolipids as previously underappreciated mediators of host metabolism and inflammation. Collectively, current evidence supports sphingolipid metabolism as a promising therapeutic target and identifies natural bioactives as potential complementary strategies for metabolic disease intervention.