Aucubin as a multifunctional iridoid glycoside: Molecular pharmacology and therapeutic mechanisms supporting its potential as a drug discovery scaffold.

Abstract

Aucubin is a widely distributed iridoid glycoside that has gained increasing attention as a multifunctional scaffold in natural product-based drug discovery. Occurring predominantly in Plataginaceae and related medicinal plant families, aucubin is biosynthesized through a modified monoterpenoid pathway and stored as a stable glycoside that undergoes enzymatic activation to yield its aglycone aucubigenin. This prodrug-like behavior underlies its context-dependent biological activity. Accumulating preclinical evidence demonstrates anti-oxidant, anti-inflammatory, anti-fibrotic, metabolic-regulatory, cytoprotective, and immunomodulatory effects across models of cardiovascular disease, diabetes, chronic kidney injury, liver fibrosis, neurodegeneration, respiratory disorders, osteoporosis, wound healing, and cancer. Mechanistically, aucubin consistently modulates convergent stress-response pathways, including suppression of NF-κB signaling, activation of Nrf2/ARE anti-oxidant defense, regulation of AMPK-mediated metabolic homeostasis, preservation of mitochondrial integrity, and inhibition of TGF-β/Smad-driven fibrogenesis. In bone and metabolic disorders, aucubin restores redox balance and supports osteoblast function while limiting osteoclastogenesis. In cancer models, it suppresses proliferation and modulates tumor-associated immune signaling, including PD-L1 expression. These pathways are central to the global burden of non-communicable diseases, directly aligning aucubin research with Sustainable Development Goal 3 (Good Health and Well-being). While the breadth and internal consistency of experimental findings support its value as a multi-target cytoprotective template, translation toward clinical application remains limited by the scarcity of human studies, standardized pharmacokinetic data, and comprehensive toxicological evaluation. Collectively, this review positions aucubin as a biologically informative iridoid glycoside with substantial scaffold-level relevance for future natural-product-inspired therapeutic development, rather than as a near-term clinical drug candidate.