2. Academic Validation
  3. Rhein alleviates renal interstitial fibrosis by inhibiting Smad3 phosphorylation in TGF- β/Smad signalling pathway

Rhein alleviates renal interstitial fibrosis by inhibiting Smad3 phosphorylation in TGF- β/Smad signalling pathway

  • Chin Herb Med. 2025 Jul 23;17(4):744-755. doi: 10.1016/j.chmed.2025.07.003.
Xiaoli Zheng 1 2,  Li Wang 1 2,  Yu Cheng 3,  Hao Lin 3,  Shundi Liu 3,  Xinjiang Chen 1,  Zheng Xiang 1 2 3
Affiliations

Affiliations

  • 1 Hangzhou Lin'an Traditional Chinese Medicine Hospital, Affiliated Hospital, Hangzhou City University, Lin'an 311300, China.
  • 2 Zhejiang Provincial Key Laboratory of Novel Targets and Drug Study for Neural Repair, School of Medicine, Hangzhou City University, Hangzhou 310015, China.
  • 3 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
PMID: 41399800 DOI: 10.1016/j.chmed.2025.07.003
Abstract

Objective: The anthraquinone compound rhein (1,8-dihydroxy-3-carboxyanthraquinone), derived from Rhei Radix et Rhizoma (rhubarb, Dahuang in Chinese), exhibits notable anti-fibrotic effects. However, the mechanisms underlying these effects have not been fully elucidated. Suppressor of mothers against decapentaplegic 3 (SMAD3) phosphorylation plays a crucial role in the canonical transforming growth factor-β (TGF-β)/Smad signalling pathway. In this study, we investigated the effect of rhein on the TGF-β/Smad signalling pathway in renal interstitial fibrosis (RIF).

Methods: A unilateral ischaemia-reperfusion injury (UIRI) rat model was employed to simulate renal injury and assess the therapeutic effect of rhein in vivo. In vitro, TGF-β1-stimulated NRK-52E rat renal epithelial cells and HK-2 human proximal tubular epithelial cells were used to mimic fibrotic conditions. Rhein's interaction with SMAD3 was further explored using molecular docking and bio-layer interferometry assays. Additionally, SMAD3 knockdown and overexpression studies were performed in HK-2 cells to elucidate the functional role of SMAD3 in rhein-mediated anti-fibrotic activity.

Results: Rhein treatment significantly improved renal function and reduced fibrosis in UIRI rats, primarily by inhibiting SMAD3 phosphorylation. Rhein treatment mitigated aberrant remodelling and extracellular matrix accumulation in both NRK-52E and HK-2 cells and in the UIRI rat model. The anti-fibrotic effects of rhein were attenuated by SMAD3 deficiency but enhanced by SMAD3 overexpression in HK-2 cells.

Conclusion: Rhein exerts its anti-fibrotic effects in renal interstitial fibrosis by targeting the TGF-β/SMAD3 signaling pathway. Acting as a natural antagonist of SMAD3, rhein offers promising potential for therapeutic development in renal fibrosis. These findings provide a new mechanistic insight for further clinical research and drug development.

Keywords

Rhei Radix et Rhizoma; Smad3; TGF-β/Smad pathway; renal interstitial fibrosis; rhein.

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