Exploring the impact of wild and cultivated environments on bioactive compounds and anti-cancer potential of mushroom Phellinus linteus through metabolomics and network pharmacology

The medicinal fungus Phellinus linteus (commonly known as “Sanghuang”) is highly regarded for its nutritional and pharmacological properties. However, its metabolic profile and therapeutic value vary significantly depending on its geographical origin, host substrate, and cultivation method. This study integrated metabolomics and network pharmacology to identify the bioactive compound profiles of Sanghuang from wild Tibetan (from mulberry, pine, and poplar hosts) and cultivated conditions (from Tibet, Fujian, and Jilin), and analyzed their potential anti-cancer mechanisms for lung and colorectal cancers. Wild samples exhibited a stress defense metabolic strategy, enriched in triterpenoids and flavonoids for environmental adaptation, whereas cultivated groups prioritized primary metabolism. Notably, cold stressed cultivated samples from Jilin exhibited a metabolic profile analogous to the wild samples. Host substrates markedly governed the differential accumulation of specific alkaloids, lipids, and saponins. Furthermore, network pharmacology identified 63 key bioactive compounds, including alisol C and wogonin, which target TP53 and EGFR via MAPK and PI3K-Akt signaling pathways against lung and colorectal cancers. Consequently, wild samples from mulberry showed better medicinal potential, while specific cultivated strains (Jilin) proved to be high-quality alternatives. These predictions were experimentally validated by CCK-8 and flow cytometry assays, demonstrating that both wild Tibet mulberry and Jilin-cultivated Sanghuang (WD_1 and CT_3) extracts inhibited the proliferation of A549 and HCT116 cells in a dose- and time-dependent manner and induced apoptosis predominantly through late apoptotic pathways. WD_1 exhibited superior cytotoxicity at high concentrations, while CT_3 showed comparable efficacy at moderate doses, corroborating its potential as a viable wild-type substitute.