Rhein: An Updated Review Concerning Its Biological Activity, Pharmacokinetics, Structure Optimization, and Future Pharmaceutical Applications

Abstract

Rhein is a natural active ingredient in traditional Chinese medicine that has attracted much attention due to its wide range of pharmacological activities. However, its clinical application is limited by low water solubility, poor oral absorption, and potential toxicity to the liver and kidneys. Recently, advanced extraction and synthesis techniques have made it possible to develop derivatives of rhein, which have better pharmacological properties and lower toxicity. This article comprehensively summarizes the biological activity and action mechanism of rhein. Notably, we found that TGF-β1 is the target of rhein improving tissue fibrosis, while NF-κB is the main target of its anti-inflammatory effect. Additionally, we reviewed the current research status of the pharmacokinetics, toxicology, structural optimization, and potential drug applications of rhein and found that the coupling and combination therapy of rhein and other active ingredients exhibit a synergistic effect, significantly enhancing therapeutic efficacy. Finally, we emphasize the necessity of further studying rhein's pharmacological mechanisms, toxicology, and development of analogs, aiming to lay the foundation for its widespread clinical application as a natural product and elucidate its prospects in modern medicine.

Keywords: NF-κB; TGF-β1; combination therapy; derivatives; pharmacokinetics; rhein; twin drug.

Figure 1

Herbal resources of rhein.

Figure 2

Hypoglycemic and lipid-lowering effects of rhein. The black arrow indicates the upward or downward adjustment, while the brown arrow indicates the causal relationship. NAFLD rats: Non-alcohol fatty liver disease; db/db and T2DM rats: Type 2 diabetes mellitus model; RMCs: Rat mesangial cells; DN-db/db rats: Diabetic nephropathy-type 2 diabetes model; DIO rats: Diet-induced obesity model.

Figure 3

The pathway in anti-inflammatory effect of rhein. The black solid line represents the parallel relationship; the grey solid line arrow represents the indirect connection; the black solid line arrow represents the causal relationship; and the black wavy line represents the crosstalk relationship.

Figure 4

The pathway in anti-fibrotic effect of rhein. The black solid line arrow represents the parallel relationship, the green solid line arrow represents the promoting relationship, and the green dashed line arrow represents the inhibiting relationship.

Figure 5

Cardiocerebral protective effect of rhein.

Figure 6

Derivatives of rhein. The blue part represents the substrates for synthesizing rhein derivatives or the substituents they provide; The red part represents the new functional groups introduced into the structure of rhein.