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Journal of Traditional Chinese Medicine >

2026 , Vol. 46 >Issue 4: 821 - 831

DOI: https://doi.org/10.19852/j.cnki.jtcm.2026.04.005

Original Articles

Yigongsan decoction (异功散) ameliorates anemia of chronic disease by attenuating mothers against decapentaplegic homolog-signal transducer and activator of transcription 3 interaction to regulate iron homeostasis

  • ZHENG Qin ,
  • ZHU Xiaoqin ,
  • HU Jie ,
  • BU Jingyang ,
  • JI Yuting ,
  • JIANG Yiling ,
  • SHI Ling ,
  • ZHANG Aiping ,
  • WU Zhihao ,
  • XU Haitao ,
  • ZHANG Ruifeng ,
  • YANG Yang ,
  • LUO Meihong
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  • 1 Department of Hematology, Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine (Baoshan Hospital, Shanghai University of Traditional Chinese Medicine), Shanghai 201999, China
    2 Department of Hematology, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China
    3 Shanghai Huating Town Community Health Service Center, Shanghai 201816, China
    4 Department of Science and Technology Experiment Center, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
First author contact:

ZHENG Qin and ZHU Xiaoqin are co-first authors and contributed equally to this work

Received date: 2025-10-06

  Accepted date: 2026-04-17

  Online published: 2026-08-08

Supported by

The Shanghai Oriental Talent Youth Program: Mechanism Study of Yigongsan Decoction in Improving Anemia of Chronic Disease by Downregulating Hepcidin Antimicrobial Peptide Through Histone Modification-mediated Crosstalk of Mothers Against Decapentaplegic Homolog/Signal Transducer and Activator of Transcription 3 Signaling Pathways(QNWS2024111);National Natural Science Foundation Youth Project: Mechanism Study of Yigongsan Decoction in Improving Iron Metabolism in Anemia of Chronic Disease by Regulating the Hepcidin-ferroportin Axis Through Activin B Competitive Binding to Bone Morphogenetic Protein Receptors(81804021);Construction of Key Medical Science (Specialty) Department in Baoshan District(BSZK-2023-Z01);Shanghai Key Discipline of Traditional Chinese Medicine (Clinical Type) Project(shzyyzdxk-2024208)

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Abstract

OBJECTIVE: To investigate how Yigongsan (异功散) decoction (YGS) regulates iron metabolism in anemia of chronic disease (ACD) by modulating the hepcidin-ferroportin axis, with particular focus on crosstalk between the mothers against decapentaplegic homolog (SMAD) and signal transducer and activator of transcription 3 (STAT3) signaling pathways.

METHODS: In vivo: a lipopolysaccharide (LPS)-induced ACD mouse model was treated with YGS (15.413 g·kg-1·d-1) for 7 d. Iron metabolism was evaluated by measuring serum and splenic iron levels, as well as hepcidin antimicrobial peptide (HAMP) and ferroportin (Fpn) mRNA expression (quantitative real-time polymerase chain reaction, qRT-PCR), and protein-protein interactions (co-immunoprecipitation, Co-IP). In vitro: HepG2 cells were stimulated with interleukin-6 (IL-6) or activin B and treated with 10% YGS-medicated serum. Iron metabolism was evaluated by intracellular and extracellular iron. STAT3/SMAD pathway activity was assessed by siRNA knockdown, Western blotting of phosphorylated SMAD1/5/8 (p-SMAD1/5/8) and phosphorylated STAT3 (p-STAT3), and Co-IP.

RESULTS: LPS-treated mice, YGS significantly decreased splenic iron content (P <0.01) and increased serum iron levels (P <0.05). Hepatic HAMP mRNA was downregulated, while Fpn mRNA was upregulated. In HepG2 cells, YGS counteracted IL-6/activin B-induced dysregulation, reducing hepcidin and intracellular iron while increasing ferroportin and extracellular iron. siRNA experiments confirmed that YGS restored the hepcidin-ferroportin balance independently of direct SMAD or STAT3 inhibition. Co-IP and immunofluorescence revealed that YGS attenuated the competitive interaction between phosphorylated SMAD1/5/8 (p-SMAD1/5/8) and phosphorylated STAT3 (p-STAT3), reducing their nuclear co-localization and subsequent HAMP transcription.

CONCLUSION: Our results suggest that YGS may alleviate ACD by attenuating the interaction between the SMAD and STAT3 pathways, which appears to lead to reduced STAT3 phosphorylation and hepcidin expression, thereby re-establishing iron homeostasis. This identifies YGS as a potential therapeutic agent targeting inflammation-induced iron dysregulation.

Key words： Smad proteins; STAT3 transcription factor; phosphorylation; anemia of chronic disease; hepcidin-ferroportin axis; Yigongsan decoction

Cite this article

ZHENG Qin , ZHU Xiaoqin , HU Jie , BU Jingyang , JI Yuting , JIANG Yiling , SHI Ling , ZHANG Aiping , WU Zhihao , XU Haitao , ZHANG Ruifeng , YANG Yang , LUO Meihong . Yigongsan decoction (异功散) ameliorates anemia of chronic disease by attenuating mothers against decapentaplegic homolog-signal transducer and activator of transcription 3 interaction to regulate iron homeostasis[J]. Journal of Traditional Chinese Medicine, 2026 , 46(4) : 821 -831 . DOI: 10.19852/j.cnki.jtcm.2026.04.005

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