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Chlorogenic acid promotes liver regeneration after partial hepatectomy through activating Nrf2 via directly targeting Keap1

Acta Pharmacologica Sinica (2026) Cite this article

Abstract

Liver regeneration (LR) is crucial for liver function recovery, but there is still no effective treatment to promote LR. Chlorogenic acid (CGA) is the main active compound of Eucommia ulmoides Oliv., which is traditionally recorded to possess liver tonifying function. Our results revealed that CGA promoted LR in mice performed with 90% and 70% partial hepatectomy (PHx). CGA activated nuclear factor erythroid 2-related factor 2 (Nrf2) through interacting with kelch-like ECH-associated protein 1 (Keap1) during LR process. Nrf2 activation initiated the mRNA expression of E2 promoter binding factor 1 (E2F1) to accelerate cell cycle progression. Moreover, Nrf2 activation also initiated the mRNA expression of peroxisome proliferative-activated receptor, gamma, coactivator 1-alpha (PGC-1α) to promote ATP production, which supplied the sufficient energy to support LR. The importance of Nrf2 was further validated in Nrf2 knockout and liver specific Keap1 genetic depletion mice. Moreover, Arg415 residue in the kelch domain of Keap1 was proved to be pivotal for the binding of CGA with Keap1. Our findings not only highlighted the critical role of Nrf2 during LR process, but also provided a solid research foundation for exploring CGA as a promising therapeutic candidate to promote LR.

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Fig. 1: CGA facilitated LR in mice after PHx.
The alternative text for this image may have been generated using AI.
Fig. 2: Nrf2 was crucial for the CGA-supplied promotion on LR.
The alternative text for this image may have been generated using AI.
Fig. 3: CGA promoted the Nrf2-dependent E2f1 mRNA expression to accelerate hepatic cell cycle progression.
The alternative text for this image may have been generated using AI.
Fig. 4: CGA increased Nrf2-dependent mRNA expression of Ppargc1a to enhance FAO process.
The alternative text for this image may have been generated using AI.
Fig. 5: CGA activated Nrf2 by directly interacting with Keap1.
The alternative text for this image may have been generated using AI.
Fig. 6: The effect of CGA on LR in liver-specifc Keap1 knockout mice.
The alternative text for this image may have been generated using AI.
Fig. 7: CGA activated Nrf2 by competitively binding to Arg415 residue in the kelch domain of Keap1.
The alternative text for this image may have been generated using AI.
Fig. 8: The summary diagram illustrates that CGA promotes LR following PHx through activating Nrf2 via directly targeting Keap1.
The alternative text for this image may have been generated using AI.

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Acknowledgements

We thank Prof Guang-bo Ge (Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine) for providing Keap1-/- Huh7 cells. We thank the staff members of the Large-scale Protein Preparation System at the National Facility for Protein Science in Shanghai (https://cstr.cn/31129.02.NFPS) for providing technical support and assistance in data collection and analysis for MST assay. This work was financially supported by the National Key R&D Program of China (2024YFC3506600), National Natural Science Foundation of China (82304845, 82273994), Program of Shanghai Academic Research Leader (23XD1404000), and the “Young Qihuang Scholar” for Li-li Ji.

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  1. These authors contributed equally: Hao-yu Xue, Xin-nan Gu

Authors and Affiliations

  1. The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Hao-yu Xue, Xin-nan Gu, Ze Zhang, Kun-yu Zhang, Zhen-lin Huang, Bin Lu, Meng-juan Wei & Li-li Ji

  2. Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    Hao-yu Xue & Jian-gao Fan

  3. School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China

    Zhuang Huang

  4. Shanghai Academy of International Standardization for Traditional Chinese Medicine, Shanghai, 201203, China

    Meng-juan Wei

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  1. Hao-yu Xue
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Contributions

LLJ conceptualized this study. HYX, XNG, ZH, ZZ, KYZ, ZLH, BL and MJW conducted the experiments and analysis the data. LLJ supervised the research. HYX and MJW drafted the manuscript. JGF and LLJ revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Meng-juan Wei or Li-li Ji.

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Xue, Hy., Gu, Xn., Huang, Z. et al. Chlorogenic acid promotes liver regeneration after partial hepatectomy through activating Nrf2 via directly targeting Keap1. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01770-4

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