Multi-Target Complementary Systems Pharmacology of a Zingiberaceae Jamu Formula (Curcuma zanthorrhiza, Curcuma longa and Zingiber officinale) in Reversing Lipotoxicity and Fibrogenesis Transcriptomics in MASH

Abstract

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by lipotoxicity, lobular inflammation and progressive fibrogenesis. Single-target agents show limited efficacy, underscoring the potential of traditional Indonesian Zingiberaceae Jamu combining Curcuma zanthorrhiza, Curcuma longa and Zingiber officinale, whose systems-level multi-target mechanisms remain undefined against human transcriptomes.

Objective: To decipher the multi-target polypharmacological complementarity of the Zingiberaceae Jamu triad against human MASH pathophysiology using clinical biopsy RNA-Seq, network pharmacology and molecular docking.

Methods: Human liver biopsy RNA-Seq transcriptomics (NCBI Gene Expression Omnibus, GEO, GSE135251; N = 216: 10 healthy controls, 51 non-alcoholic fatty liver [NAFL], 155 MASH fibrosis stages F0–F4) were integrated with bioactive metabolite profiling (Lipinski Rule of Five and Veber oral bioavailability), target prediction, protein–protein interaction (PPI) topology, KEGG enrichment and AutoDock Vina molecular docking.

Results: Biopsy analysis identified 1,842 differentially expressed genes (DEGs; 1,024 upregulated, 818 downregulated), with upregulation of fibrogenic (COL1A1, TIMP1, ACTA2, TGFB1) and inflammatory genes (CCL2, CXCL8, TNF) alongside suppression of fatty acid oxidation regulators (PPARA, CPT1A, ACOX1). Intersection of 24 bioavailable phytochemicals with MASH DEGs yielded 126 shared targets (PPI: 126 nodes, 1,142 edges, average degree 18.13). Six master hub genes were identified: PPARG (degree 84), TNF (78), AKT1 (76), TGFBR1 (68), RELA (64) and MMP9 (58). Docking predicted spontaneous binding: curcumin to PPARG (ΔG = −9.4 kcal/mol) and AKT1 (−8.8); xanthorrhizol to TNF-α (−8.2); 6-shogaol to TGFBR1 (−8.6) and MMP9 (−8.4).

Conclusion: The findings are consistent with a tri-pillar polypharmacological complementarity in the Zingiberaceae Jamu formula and establish a rational mechanistic framework for standardized phytopharmaceutical development against human MASH.