Sirt1 attenuates calcific aortic valve disease by inhibiting ferroptosis and enhancing mitochondrial function via the activation of the Nrf2/HO‑1/FTH1 axis.

Authors

Fei Yan, Lei Shi, Yuechan Wang, Ying Zhao, Yuanyuan Wu, Dubiao Xian, Yunheng Liang, Ning Wang, Hongwang Cui, Minni Zhang

Published in

International journal of molecular medicine. Volume 58. Issue 5. Epub Sep 25, 2026.

Abstract

Calcific aortic valve disease (CAVD) is a progressive disorder characterized by valvular calcification and currently lacks effective pharmacological therapies. Sirtuin 1 (Sirt1) has emerged as a cardioprotective factor; however, its role in CAVD remains unclear. The present study aimed to investigate whether Sirt1 attenuates CAVD by regulating iron homeostasis, ferroptosis and mitochondrial function through the nuclear factor erythroid 2‑related factor 2 (Nrf2)/heme oxygenase‑1 (HO‑1)/ferritin heavy chain 1 (FTH1) signaling axis. Sirt1 expression was evaluated in human calcified and non‑calcified aortic valves. Primary human aortic valve interstitial cells (hAVICs) were transfected with pcDNA3.1‑Sirt1 and subjected to osteogenic induction with or without the Nrf2 inhibitor, ML385, or the ferroptosis inducer, erastin. Osteogenic differentiation, mitochondrial function, ferroptosis and Nrf2/HO‑1/FTH1 signaling were analyzed. In vivo, apolipoprotein E‑deficient (Apoe‑/‑) mice fed a Western diet containing 21% fat and 0.15% cholesterol (w/w) were treated with the Sirt1 agonist, SRT2104, with or without AAV‑mediated HO‑1 or FTH1 silencing, to evaluate aortic valve calcification. The results revealed that Sirt1 expression was significantly reduced in calcified human valves and osteogenically induced hAVICs. Sirt1 overexpression inhibited osteogenic differentiation, reduced RUNX2 nuclear translocation, restored mitochondrial function and suppressed ferroptosis. Mechanistically, Sirt1 activated Nrf2/HO‑1 signaling, upregulated the downstream effector, FTH1, reduced intracellular Fe2+ accumulation and maintained iron homeostasis. These protective effects were abolished by treatment with ML385 or erastin. In Apoe‑/‑ mice, SRT2104 attenuated aortic valve calcification and pathological remodeling, whereas HO‑1 or FTH1 silencing partially reversed these benefits. Collectively, the present study demonstrates that Sirt1 protects against CAVD by activating the Nrf2/HO‑1 pathway, leading to the FTH1‑dependent maintenance of iron homeostasis, the suppression of ferroptosis, the preservation of mitochondrial function and the inhibition of osteogenic differentiation. These findings identify the Sirt1/Nrf2/HO‑1/FTH1 axis as a potential therapeutic target for CAVD.

PMID:
42788342
Bibliographic data and abstract were imported from PubMed on 25 Sep 2026.

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