2. Academic Validation
  3. Myricanol represses renal fibrosis by activating TFAM and ZNRF1 to inhibit tubular epithelial cells ferroptosis

Myricanol represses renal fibrosis by activating TFAM and ZNRF1 to inhibit tubular epithelial cells ferroptosis

  • Eur J Pharmacol. 2024 Dec 5:984:176999. doi: 10.1016/j.ejphar.2024.176999.
Min Zheng 1,  Qiao Jiang 1,  Junxiong You 2,  Baogui Gao 2,  Weiwei Cui 3,  Wanyu Yao 2,  Fengqing Su 1,  Xuegang Sun 4,  Lei La 5
Affiliations

Affiliations

  • 1 Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 2 The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Imaging, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 4 The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China. Electronic address: sxg_smu@126.com.
  • 5 Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. Electronic address: lalei@smu.edu.cn.
PMID: 39349116 DOI: 10.1016/j.ejphar.2024.176999
Abstract

Background: Mitochondrial dysfunction induces Ferroptosis in renal tubular epithelial cells (TECs). Studies have shown that myricanol maintains muscle cell function by enhancing mitochondrial energy metabolism.

Hypothesis: Myricanol delays renal fibrosis by maintaining mitochondrial integrity and inhibiting Ferroptosis in TECs.

Methods: Mice kidney lacking mitochondrial transcription factor A (TFAM), blood specimens, or pathological sections of renal tissue from patients with renal failure were used to explore the relationship between mitochondrial and renal functions. Erastin induced-TECs Ferroptosis was used to study the potential mechanism by which TFAM regulates renal fibrosis. Chronic kidney disease (CKD) mice were utilized to explore the anti-fibrotic effects of myricanol.

Results: The number of mitochondria and TFAM expression were decreased in human blood samples and pathological sections. Renal TFAM-deficient mice exhibited abnormalities in renal function, including Ferroptosis and fibrosis. Ferrostatin-1 significantly inhibited renal fibrosis by preventing TECs Ferroptosis. Transcriptional Sequencing results indicated that zinc and ring finger 1 (ZNRF1) were important downstream genes of TFAM that regulate Ferroptosis. We demonstrated that TFAM deficiency and Ferroptosis, which destroyed interaction between ZNRF1 and the iron transport-related protein lipocalin-2 (LCN2), but myricanol clould reverse this effect. Overexpression of ZNRF1 efficiently maintained mitochondrial integrity and inhibited renal fibrosis. Myricanol ameliorated transforming growth factor β1-induced mitochondrial impairment. We firstly confirmed that myricanol efficiently improved renal function and suppresses fibrosis in CKD mice.

Conclusions: Myricanol efficiently inhibit fibrosis through activating TFAM to stimulate the interaction between ZNRF1 and LCN2.

Keywords

Ferroptosis; LCN2; Myricanol; Renal fibrosis; TFAM; ZNRF1.

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