Emodin and the Anthraquinone Scaffold: Therapeutic Promise and Strategies to Overcome Translational Barriers

Emodin, a trihydroxy-methyl anthraquinone abundant in rhubarb, <i>Polygonum</i> species, and other medicinal plants, exemplifies the therapeutic potential and translational complexity of the broader anthraquinone scaffold. Anthraquinone derivatives have demonstrated antiproliferative, anti-inflammatory, metabolic, cardiovascular, antifibrotic, and immunomodulatory effects, consistently reported across diverse preclinical models, targeting pathways such as NF-κB, PI3K/AKT, MAPKs, AMPK, PPARs, NLRP3, and ferroptosis-related axes. Despite strong preclinical efficacy, clinical development has been limited by unfavorable absorption, distribution, metabolism, and excretion (ADME) characteristics, including poor aqueous solubility, extensive first-pass glucuronidation, and active efflux via intestinal and hepatic transporters. These features result in low and variable systemic exposure, while high local concentrations, particularly in the gastrointestinal tract, contribute to context-dependent toxicity signals that complicate risk assessment. The present review integrates pharmacological, toxicological, and formulation-focused evidence to provide a unified assessment of emodin and the anthraquinone scaffold. Particular emphasis is placed on bidirectional, dose- and context-dependent effects on the liver and kidney; the modulation of cytochrome P450 enzymes, UGTs, and transporters; and emerging preclinical formulation strategies that aim to decouple intrinsic bioactivity from pharmacokinetic limitations.