Bee venom bioactive compounds as multi-target anti-inflammatory therapeutics: a comprehensive review of molecular mechanisms, network pharmacology, molecular docking, and nano-formulated delivery

Abstract Inflammation is one of the main underlying causes of many diseases. Despite the fact that existing anti-inflammatory treatments like NSAIDs and corticosteroids can effectively treat inflammation, the use of these medicines clinically poses several problems due to serious side effects and poor specificity. Bee venom (BV) has emerged as a promising natural treatment for its anti-inflammatory and immunomodulatory properties due to the presence of biologically active compounds such as melittin and phospholipase A2 (PLA2). BV modulates multiple inflammatory signaling pathways by inhibiting NF-κB activation, suppressing MAPK signaling, downregulating inducible nitric oxide synthase (iNOS) and cyclooxygenase−2 (COX-2), promoting regulatory T-cell (Treg) polarization, and activating the Nrf2/HO-1 antioxidant pathways. Furthermore, BV enhances wound healing by macrophage polarization, regulation of NF-κB, MAPK, Nrf2/HO-1, and ROS signaling, inhibition of PI3K/Akt signaling, suppression of TGF-β-induced pro-fibrotic gene expression, and cytokine modulation to promote tissue regeneration. The therapeutic efficacy of BV constituents has been increased due to the recent advancement in the field of nanotechnology by improving the stability, bioavailability, targeted delivery, and toxicity. In the context of parallel network pharmacology, PPI network analysis, GO enrichment, KEGG pathway analysis, molecular docking studies, and molecular dynamics simulation have shed light on the interactions of BV constituents with various inflammatory peptides. By integrating molecular pharmacology, nanomedicine, and computational approaches, this review provides a comprehensive overview of the therapeutic potential of BV bioactive compounds and highlights future opportunities for their development as multi-target anti-inflammatory candidates. However, further experimental and clinical studies are required to establish their efficacy, safety, pharmacokinetic profiles, and therapeutic applicability.