Biomarkers for Health Functional Foods in Metabolic Dysfunction-Associated Steatotic Liver Disorder (MASLD) Prevention: An Integrative Analysis of Network Pharmacology, Gut Microbiota, and Multi-Omics

Abstract

Metabolic dysfunction-associated steatotic liver disorder (MASLD) is increasingly prevalent globally, highlighting the need for preventive strategies and early interventions. This comprehensive review explores the potential of health functional foods (HFFs) to maintain healthy liver function and prevent MASLD through an integrative analysis of network pharmacology, gut microbiota, and multi-omics approaches. We first examined the biomarkers associated with MASLD, emphasizing the complex interplay of genetic, environmental, and lifestyle factors. We then applied network pharmacology to identify food components with potential beneficial effects on liver health and metabolic function, elucidating their action mechanisms. This review identifies and evaluates strategies for halting or reversing the development of steatotic liver disease in the early stages, as well as biomarkers that can evaluate the success or failure of such strategies. The crucial role of the gut microbiota and its metabolites for MASLD prevention and metabolic homeostasis is discussed. We also cover state-of-the-art omics approaches, including transcriptomics, metabolomics, and integrated multi-omics analyses, in research on preventing MASLD. These advanced technologies provide deeper insights into physiological mechanisms and potential biomarkers for HFF development. The review concludes by proposing an integrated approach for developing HFFs targeting MASLD prevention, considering the Korean regulatory framework. We outline future research directions that bridge the gap between basic science and practical applications in health functional food development. This narrative review provides a foundation for researchers and food industry professionals interested in developing HFFs to support liver health. Emphasis is placed on maintaining metabolic balance and focusing on prevention and early-stage intervention strategies.

Keywords: HFFs; gut microbiota; metabolic dysfunction-associated steatotic liver disease; omics approach.

Figure 1

Flowchart of the research process for developing health functional foods (HFFs) to treat metabolic dysfunction-associated steatotic liver disorder (MASLD) using network pharmacology.

Figure 2

Gut microbiota and their metabolites in metabolic dysfunction-associated steatotic liver disorder (MASLD) progression. Schematic representation of gut microbiota dysbiosis and its impact on liver health in MASLD. Dysbiosis is characterized by a decreased abundance of Coprococcus, Eubacterium, Lachnospiraceae, and Faecalibacterium, with increased Acidaminococcus and Escherichia. This imbalance leads to elevated production of lipopolysaccharide (LPS) and trimethylamine (TMA). LPS activates Kupffer cells via Toll-like receptor 4 (TLR4), triggering the histone deacetylase (HDAC), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and causing inflammation. TMA is oxidized to trimethylamine N-oxide (TMAO) by flavin-containing monooxygenase 3 (FMO3), interfering with cholesterol and bile acid metabolism. Short-chain fatty acids (SCFAs) promote gluconeogenesis, whereas bile acids interact with the farnesoid X receptor (FXR) receptor, inhibiting sterol regulatory element binding protein 1c (SREBP-1c) and affecting lipogenesis and fatty acid β-oxidation. Green arrows indicate positive effects; red lines represent inhibitory actions. The dashed line shows the enterohepatic circulation of bile acids. This figure highlights the intricate relationship between gut microbiota, their metabolites, and liver function in MASLD progression. Up and down arrows indicated the increase and decrease of the function.

Figure 3

Transcriptomics, metabolomics, and microbiomics in metabolic dysfunction-associated steatotic liver disorder (MASLD). This figure illustrates the interplay between transcriptomics, metabolomics, and the gut–liver axis in MASLD etiology. Transcriptomics: lncRNAs (NEAT1, MRAK052686) promote fatty degeneration via c-Jun N-terminal kinases (JNK)/sterol regulatory element binding protein 1c (SREBP-1c) and nuclear factor erythroid-2-related factor 2 (Nrf2) pathways; miRNAs (miR-379, miR-212-5p, miR-122) negatively impact insulin-like growth factor (IGF)-1 signaling and AMP kinase (AMPK); circRNAs (circSCD1, circ_0057558) influence lipid metabolism through Janus Kinase2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) and miR-206 pathways. Metabolomics: shows hepatic changes including tricarboxylic acid cycle anaplerosis, elevated lactate and gluconeogenesis, and synthesis of saturated sphingolipids and plasma eicosanoids. Gut–liver axis: microbial metabolites affect liver function via Toll-like receptor 4 (TLR4), histone deacetylases (HDACs), and farnesoid X receptor (FXR) pathways. Green arrows indicate positive regulatory effects; red arrows represent negative impacts. This figure demonstrates the complex molecular interactions underlying MASLD progression.