Network Diffusion on a Multiscale Interactome Reveals Novel Herbal Candidates and Bioactive Compounds Converging on Shared Effectors in Anemia

Anemia is a prevalent hematological disorder driven by heterogeneous mechanisms-iron deficiency, chronic inflammation, impaired erythropoiesis, and hemolysis-that single-target therapies often fail to address. We systematically prioritized candidate herbs and their active compounds for anemia using a multiscale interactome-based network pharmacology framework.

Herb-compound-target data were aggregated from OASIS, DrugBank, TTD, and STITCH; anemia disease targets came from DisGeNET. We generated diffusion profiles using a biased random walk with restart on the tripartite multiscale interactome, and ranked herbs by cosine similarity to the anemia profile. Hypergeometric testing, GO/KEGG enrichment, compound-level subnetwork analysis, and HERB-based transcriptome validation followed.

The top 10 prioritized herbs-led by Swertiae Herba, Geranii Herba, and Salviae Miltiorrhizae Radix-were enriched in TNF/NF-κB, HIF-1, and JAK-STAT/PI3K-Akt pathways. Four high-ranking herbs and seven constituent compounds (e.g., swertiamarin, p-hydroxybenzoic acid, physcion, salvianolic acids A/B) had not previously been proposed as therapeutic candidates for anemia. Transcriptome validation of tanshinone IIA implicated the cell cycle, PI3KAkt, and FoxO pathways and recovered GDF15 and CXCL12.

Across all subnetworks, divergent compound-target architectures converged on shared downstream effectors (PLEC, ITGB4, ELANE, TNF), supporting a multi-target paradigm. Mechanistic profiles further suggested subtype relevance: swertiamarin to inflammation-associated anemia; p-hydroxybenzoic acid to telomere/bone-marrow-failure anemias; physcion/epicatechin to oxidative-stress and hemolytic anemias.

The framework offers a reproducible route to nominating multi-target herbal therapeutics for anemia, identifying novel candidates that warrant experimental validation.