Chlorogenic acid promotes liver regeneration after partial hepatectomy through activating Nrf2 via directly targeting Keap1.
Xue Hao-Yu, Gu Xin-Nan, Huang Zhuang, Zhang Ze, Zhang Kun-Yu, Huang Zhen-Lin, Lu Bin, Fan Jian-Gao, Wei Meng-Juan, Ji Li-Li
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.
Key Findings
- Chlorogenic acid (CGA) promotes liver regeneration in mice after partial hepatectomy by activating Nrf2.
- CGA activates Nrf2 through direct interaction with Keap1, specifically involving the Arg415 residue in Keap1's kelch domain.
- Nrf2 activation induces expression of E2F1 to accelerate cell cycle progression and PGC-1α to enhance ATP production, supporting liver regeneration.
Clinical Significance
These findings suggest that chlorogenic acid is a promising therapeutic candidate for enhancing liver regeneration after surgery, potentially improving recovery outcomes in patients undergoing partial hepatectomy.
Citation
Xue Hao-Yu, Gu Xin-Nan, Huang Zhuanget al.. Chlorogenic acid promotes liver regeneration after partial hepatectomy through activating Nrf2 via directly targeting Keap1. Acta pharmacologica Sinica. 2026-Mar-20.