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.