Structural diversity and therapeutic potential of phenanthrenes from the Dendrobium genus: a comprehensive review...

For millennia, Dendrobium Sw., the second-largest genus of Orchidaceae, has been widely applied in traditional Chinese medicine to nourish yin, clear heat, and promote body fluid. Its stems are a rich source of phenanthrenes, which are low molecular weight polycyclic aromatic metabolites with remarkable structural diversity and broad-spectrum bioactivities. This review provides the first comprehensive and systematic analysis of 158 naturally occurring phenanthrenes isolated from 53 Dendrobium taxa (51 species, 1 variety, and 1 horticultural cultivar) based on an extensive literature survey of international and Chinese databases (PubMed, Web of Science, SciFinder, CNKI, etc.) from 1987 to 2025. The article summarizes pharmacopoeial records, classical texts, and theses. The identified metabolites include simple phenanthrenes, 9,10-dihydrophenanthrenes, diphenanthrene dimers, phenanthrenequinones, and other phenanthrene derivatives, often functionalized with hydroxyl, methoxyl, and carboxyl functionalities. Among 158 phenanthrene metabolites isolated from Dendrobium species, 64 compounds (40.5%) have been evaluated in at least one bioactivity assay, with reported activities spanning anti-tumor (cytotoxic), anti-inflammatory, antioxidant, antidiabetic, anti-fibrotic, antiplatelet, or antimicrobial endpoints. However, the majority (54/64, 84.4%) are supported solely by in vitro screening data (IC₅₀ < 100 μM in cell-based assays), while only 8 compounds (12.5%) have validated mechanisms and a mere 4 compounds (6.2%) demonstrate in vivo efficacy in animal models. This quantitative summary reflects research intensity rather than therapeutic potential, given significant heterogeneity in assay systems and the absence of standardized activity thresholds across studies. Mechanistic studies have revealed that these compounds modulate key signaling. thereby offering therapeutic potential against cancer, diabetes mellitus, metabolic dysfunction-associated fatty liver disease (MAFLD), osteoarthritis, and thrombosis. Despite the bioactivity profile, clinical translation is limited by in vivo validation and the lack of pharmacokinetic data. Future studies should focus on systematic preclinical evaluation. Multi-omics mechanistic studies are needed to advance these natural scaffolds into clinically viable therapeutics.