Comprehensive metabolomic profiling of Egyptian Salvia species reveals promising leads for chemopreventive and anti-inflammatory drug development: In vitro and In silico study

The vast majority of human malignancies are the result of sustained inflammatory responses. Nowadays, it is well-known that there is a substantial association between inflammation and cancer. The Salvia genus has garnered attention due to its richness of phytochemical profiles with anti-inflammatory and chemopreventive properties. Although the recognized therapeutic potential of Salvia species is recognized, there is considerable variation in their reported chemical composition, and less is known about their compositional differences. In this work, UPLC-HRMS/MS coupled with molecular networking was employed to glean a holistic overview of the chemodiversity of the metabolome of three Salvia species. This was followed by molecular docking of 218 compounds against KEAP1 (PDB: 4IQK) and iNOS (PDB: 1M8D), validated by positive controls. Network pharmacology, Protein-Protein Interaction (PPI), and enrichment analyses identified hub genes (TNF, CASP3, CASP8, PARP1, iNOS, EGFR, PPARG, AKR1C isoforms, and NQO1) linked to inflammatory and antioxidant signaling. Docking analysis predicted that several major compounds may exhibit dual binding affinities, supported by chemoinformatics, ADME, and toxicity predictions. Cirsimaritin was evaluated against AKR1C3 and PARP1 using molecular docking and 100-ns molecular dynamics simulations, representing different stability and interaction profiles between the two targets. The results indicate a dual binding activity, with Cirsimaritin exhibiting primary and stable interaction with AKR1C3 alongside a secondary, dynamic modulatory interaction with PARP1. Mostly bioactive compounds were predominantly found in Salvia multicaulis. The extracts were screened for their in vitro anti-inflammatory and chemoprevention activities. Preliminary experiments confirmed that S. multicaulis acts as an inducer of chemopreventive NAD(P)H: Quinone oxidoreductase 1 (NQO1) protein expression in a murine hepatoma (Hepa1c1c7) chemoprevention model. It also demonstrated the ability to inhibit the lipopolysaccharides (LPS)-induced nitric oxide (NO) production and iNOS protein expression in the RAW264.7 macrophage model. Furthermore, flavonoids and terpenoids were identified to be the major components in this extract, which might be responsible for anti-inflammatory and chemoprevention activities. Our results support the possible application of S. multicaulis in the treatment of human malignancies.