Targeting metabolic syndrome with ALIAmides: A novel multi-mechanistic approach.

Metabolic syndrome (MetS) represents a growing clinical challenge worldwide, significantly increasing cardiovascular disease and type 2 diabetes risk, and all-cause mortality. Defined by a constellation of risk factors, including central obesity, dyslipidemia, hypertension, and insulin resistance, MetS is frequently associated with hepatic involvement such as metabolic dysfunction-associated fatty liver disease (MAFLD) and non-alcoholic steatohepatitis (NASH). A growing body of evidence also highlights intestinal barrier dysfunction called "leaky-gut syndrome" and gut microbiota dysbiosis as key contributors to the chronic low-grade inflammation that underlies MetS. Current therapies, including statins, GLP-1 receptor agonists, SGLT2 inhibitors, and antihypertensives, target individual components of the syndrome but fail to address its multifactorial pathophysiology. Additionally, these therapies often demonstrate tolerability issues, limited long-term adherence and compliance, and potential side effects particularly in hepatic and metabolic contexts. ALIAmides such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are emerging as promising adjunctive agents for MetS. By activating PPARs, modulating immune responses, and restoring gut barrier integrity, these compounds provide a multi-targeted strategy that addresses the complex pathophysiology of MetS. This review summarizes current evidence on ALIAmides, highlighting their potential to complement standard care and improve long-term metabolic outcomes.