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

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.