Phytochemical Profiling and Pharmacoinformatics Reveal Proliverenol from Phaleria macrocarpa as a Multi-Target Hepatoprotective Modulator of MAFLD

<b>Background:</b> Metabolic dysfunction-associated fatty liver disease (MAFLD) is a highly prevalent chronic liver disorder driven by complex metabolic, inflammatory, and oxidative mechanisms with no effective pharmacological therapy currently available. Although the multi-target natural product Proliverenol, derived from <i>Phaleria macrocarpa</i> pericarp, has shown hepatoprotective potential in preclinical and early clinical studies, its molecular mechanisms in MAFLD remain unclear. <b>Objective:</b> This study aimed to elucidate the multi-target hepatoprotective mechanisms of Proliverenol in MAFLD by integrating untargeted phytochemical profiling, network pharmacology, and molecular docking approaches. <b>Methods:</b> Untargeted LC-HRMS/MS analysis was performed to characterize the phytochemical composition of Proliverenol (Veprolin™). Identified compounds were subjected to target fishing, followed by protein-protein interaction (PPI) network construction, cluster analysis, and functional enrichment (GO and KEGG). Key MAFLD-related targets were further validated using molecular docking against major signaling proteins implicated in inflammation, apoptosis, and metabolic regulation. <b>Results:</b> Fourteen bioactive compounds were annotated, dominated by flavonoids and organic acids, including several phenolic acid derivatives, with phalerin as the most abundant constituent. Network pharmacology identified overlapping targets between Proliverenol, MAFLD, and hepatotoxicity, forming a highly interconnected PPI network. Functional enrichment revealed significant involvement in apoptosis regulation, inflammatory signaling, oxidative stress response, lipid metabolism, and insulin resistance pathways. Molecular docking demonstrated strong binding affinities of several Proliverenol constituents-particularly cucumerin B, artoindonesianin P, and vitexin 2″-p-hydroxybenzoate-toward key targets including PTGS2, SIRT1, GSK3B, RELA, and MCL1, with affinities comparable to or exceeding those of reference drugs. <b>Conclusions:</b> Proliverenol exerts hepatoprotective effects through coordinated multi-target modulation of inflammatory, metabolic, and apoptotic pathways relevant to MAFLD. While these findings provide mechanistic insights based on integrative metabolomics and computational analyses, the absence of direct experimental validation represents an important limitation. Therefore, further in vitro, in vivo, and clinical investigations are warranted to confirm the predicted molecular interactions and therapeutic relevance.