Salacca zalacca Skin as a Potential Adjuvant for Metabolic Syndrome Therapy: Integrative In Vitro and Computational Approaches

Metabolic syndrome (MetS) remains a health concern condition characterized by hyperglycemia, obesity, and hypertension, requiring effective interventions such as antioxidant support and inhibition of digestive enzymes. Salacca zalacca skin (SZS), traditionally used for its antioxidant, anti-inflammatory, and lipid-lowering properties, shows promise in addressing MetS, though its molecular mechanisms remain underexplored. This study evaluated the potential of ethanol extract of SZS in managing MetS through in vitro and in silico approaches. LC-MS/MS analysis identified 16 bioactive compounds. Network pharmacology and molecular docking revealed that diphyllin, 19-norandosterone, and anastrozole exhibited strong and stable binding affinities to MetS-related targets: TNF-α (−6.7, –6.6, and –6.1 kcal/mol) and PPARG (−7.4, –7.1, and –7.9 kcal/mol), supported by molecular dynamics simulations. Antioxidant assays demonstrated moderate activity, with EC₅₀ values of 776.4 µg/mL (ABTS) and 647.8 µg/mL (DPPH). SZS inhibited lipase (EC₅₀ = 4,330 µg/mL) and α-glucosidase (EC₅₀ = 481.1 µg/mL), indicating its potential to regulate lipid and glucose metabolism. These findings suggest that SZS may exert multi-targeted effects by scavenging free radicals, inhibiting digestive enzymes, and modulating inflammatory and metabolic pathways. This study is the 1st to integrate in vitro and in silico evidence for SZS in MetS management, laying the groundwork for its development as a nutraceutical. Future research should focus on formulation refinement, compound synergy, and long-term clinical validation. HIGHLIGHTS Sixteen bioactive compounds from SZS identified via LC-MS/MS Q-ToF. Dyphyllin shows strong and stable binding to TNF-α and PPARG proteins. The enhanced antioxidant activity of SZS, along with its ability to inhibit lipase and α-glucosidase, suggests a potential role in modulating and managing metabolic syndrome (MetS). SZS demonstrates potential as an adjuvant agent, with the ability to synergize with existing metabolic syndrome (MetS) therapies to enhance disease management and therapeutic outcomes. GRAPHICAL ABSTRACT