2. Academic Validation
  3. Baicalein Induces Hepatic Stellate Cell Senescence and Attenuates Liver Fibrosis via CEBPZ/p53/HK2-Mediated Glycolysis Inhibition

Baicalein Induces Hepatic Stellate Cell Senescence and Attenuates Liver Fibrosis via CEBPZ/p53/HK2-Mediated Glycolysis Inhibition

  • Phytomedicine. 2025 Sep 3:148:157222. doi: 10.1016/j.phymed.2025.157222.
Shuling Chen 1,  Ruiqi Li 2,  Caiyun Zhang 3,  Jun Guo 4,  Anyin Yang 5,  Dawei Yang 6,  Tianhao Mao 3,  Hongli Liu 2,  Hao Ren 4,  Zihao Liang 7,  Wei Chen 7,  Changhua Yi 7,  Qingfang Xiong 4,  Dandan Yin 8,  Xixuan Wang 9,  Yongfeng Yang 10
Affiliations

Affiliations

  • 1 Department of Hepatology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu, China; Department of Pharmacy, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210000, China.
  • 2 Department of Hepatology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu, China; Medical School, Southeast University, Nanjing 210000, Jiangsu, China.
  • 3 Nanjing Key Laboratory of Hepatology, Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu, China.
  • 4 Department of Hepatology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu, China.
  • 5 Department of Pharmacy, Gaochun Hospital Affiliated to Jiangsu University, Nanjing 210000, Jiangsu, China.
  • 6 Department of Pharmacy, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210000, China.
  • 7 Clinical Research Centre, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 8 Clinical Research Centre, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. Electronic address: jsnydandan@njucm.edu.cn.
  • 9 Department of Hepatology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu, China; Medical School, Southeast University, Nanjing 210000, Jiangsu, China. Electronic address: wxxshine@126.com.
  • 10 Department of Hepatology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu, China; Nanjing Key Laboratory of Hepatology, Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu, China. Electronic address: yyf1997@163.com.
PMID: 41075517 DOI: 10.1016/j.phymed.2025.157222
Abstract

Background: Liver fibrosis progresses to life-threatening cirrhosis, yet effective therapies remain limited. Baicalein (BA), a bioactive flavonoid, shows anti-tumor potential but its anti-liver-fibrotic efficacy is completely unexplored.

Purpose: This study aimed to investigate the anti-liver-fibrotic efficacy of BA and elucidate its underlying molecular mechanisms.

Methods: We employed carbon tetrachloride (CCl4)-induced fibrotic mice and transforming growth factor-β1-activated LX-2 human hepatic stellate cells (HSC). Comprehensive assessments included: serum biochemical analysis, histopathological examination, immunofluorescence/immunohistochemistry, the analysis of cell senescence staining, glycolytic flux assays, the assessment of the target of BA and the validation of liquid-liquid phase separation (LLPS).

Results: BA significantly attenuated liver injury (AST and AST decreasing, P < 0.001), inflammation (interleukin-6, interleukin-8 and tumor necrosis factor-alpha decreasing, P < 0.001) and Collagen deposition (P < 0.001) in fibrotic mice. In activated HSCs, BA suppressed cellular activation while inducing senescence through G1-phase cell cycle arrest (P < 0.001) and glycolysis inhibition (lactate decreasing: P < 0.001). Mechanistically, BA directly bound to CEBPZ, suppressing its LLPS and subsequently enhancing TP53 transcription. This activation of the p53/HK2 axis drove HSCs senescence and attenuated fibrosis. Critically, pharmacological inhibition of p53 with pifithrin-α hydrobromide abolished BA's anti-fibrotic effects. BA's anti-fibrotic efficacy was entirely lost in CEBPZ-knockdown models (P > 0.05), confirming the essentiality and novelty of this target.

Conclusion: Our study revealed, for the first time, that BA ameliorated liver fibrosis by directly targeting CEBPZ, disrupting its LLPS, and activating the p53/HK2 axis to induce HSC senescence. This work uncovered a novel plant-derived therapeutic strategy targeting a previously unrecognized CEBPZ-LLPS/p53/HK2 mechanism in hepatic fibrosis.

Keywords

Baicalein; CEBPZ; Hepatic stellate cells; Liver fibrosis; Senescence; p53.

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