2. Academic Validation
  3. Protocatechuic acid relieves ferroptosis in hepatic lipotoxicity and steatosis via regulating NRF2 signaling pathway

Protocatechuic acid relieves ferroptosis in hepatic lipotoxicity and steatosis via regulating NRF2 signaling pathway

  • Cell Biol Toxicol. 2024 Nov 26;40(1):104. doi: 10.1007/s10565-024-09953-7.
Yetong Feng # 1 2 3,  Mengjiao Shi # 1 2 4,  Yi Zhang # 2 4,  Xinyan Li 2 4,  Liangwen Yan 2 4,  Jiayi Xu 2 4,  Chenyue Liu 5,  Miaomiao Li 2 6,  Fengyun Bai 7,  Fenyue Yuan 7,  Ying Sun 7,  Rongrong Liu 2 4,  Yaping Zhao 2 4,  Lan Yang 1 2,  Yinggang Zhang 2 4,  Ying Guo 2 4,  Jian Zhang 8 9,  Rui Zhou 10 11,  Pengfei Liu 12 13 14
Affiliations

Affiliations

  • 1 Department of General Surgery, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 International Joint Research Center On Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 3 Core Research Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 4 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second, Xi'an, China.
  • 5 Department of Medical Image, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 6 Department of Regenerative Medicine, School of Pharmaceutical Science, Jilin University, Changchun, China.
  • 7 Shaanxi Dongtai Pharmaceutical Co., LTD, Xianyang, China.
  • 8 Department of General Surgery, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. zhangjian_xjtu@126.com.
  • 9 International Joint Research Center On Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. zhangjian_xjtu@126.com.
  • 10 Department of General Surgery, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. zhourui0317@163.com.
  • 11 International Joint Research Center On Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. zhourui0317@163.com.
  • 12 International Joint Research Center On Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. liupengfei@xjtu.edu.cn.
  • 13 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second, Xi'an, China. liupengfei@xjtu.edu.cn.
  • 14 Key Laboratory of Environment and Genes Related To Diseases, Ministry of Education of China, Xi'an Jiaotong University, Xi'an, China. liupengfei@xjtu.edu.cn.
  • # Contributed equally.
PMID: 39589556 DOI: 10.1007/s10565-024-09953-7
Abstract

Ferroptosis represents a newly programmed cell death, and the process is usually accompanied with iron-dependent lipid peroxidation. Importantly, Ferroptosis is implicated in a myriad of diseases. Recent literature suggests a potential position of Ferroptosis in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD), the most widespread liver ailment worldwide. Intriguingly, several functional genes and metabolic pathways central to Ferroptosis are regulated by nuclear factor erythroid-derived 2-like 2 (NRF2). In current work, we aim to identify protocatechuic acid (PCA), a primary metabolite of antioxidant Polyphenols, as a potent NRF2 activator and Ferroptosis inhibitor in the hepatic lipotoxicity and steatosis models. Herein, both NRF2+/+ and NRF2-/- cell lines and mice were used to analyze the importance of NRF2 in PCA function, and hepatic lipotoxicity and steatosis models were induced by palmitic acid and high-fat diet respectively. Our results indicated that Ferroptosis was mitigated by PCA intervention in hepatic cells. Furthermore, PCA exhibited therapeutic efficacy against Ferroptosis, as well as hepatic lipotoxicity and steatosis. The protective role of PCA was predominantly mediated through NRF2 activation, potentially elucidating a pivotal mechanism underlying PCA's therapeutic impact on MAFLD. Additionally, the augmented mitochondrial TCA cycle activity observed in hepatic lipotoxicity and steatosis models was ameliorated by PCA, in part via NRF2-dependent pathways, further bolstering PCA's anti-ferroptosis properties. Collectively, our findings underscore PCA's potential in alleviating hepatic Ferroptosis, lipotoxicity and steatosis via inducing activation of NRF2 signaling pathway, offering a promising strategy for the therapy of MAFLD as well as related lipid metabolic disorders.

Keywords

Ferroptosis; Lipotoxicity; NRF2; Nonalcoholic fatty liver disease; Protocatechuic acid.

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