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The cysteine metabolic regulation through CSE-transsulfuration pathway is essential in iron-induced oxidative damage of heart
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DOI：10.1080/13510002.2026.2684348.png)
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Abstract
En 中文
Iron overload (IO) cardiomyopathy is a major cause of mortality in patients with iron overload disorders. This study investigates the role of cystathionine γ-lyase (CSE), a key enzyme in the transsulfuration pathway for cysteine and hydrogen sulfide (H2S) production, in iron-induced oxidative cardiac injury.
We investigated the effects of CSE on oxidative stress, metabolic dysregulation, and cardiac remodeling using in vivo mouse models of chronic iron overload and in vitro ferric citrate (FAC)-treated cardiomyocytes.
Genetic deletion of Cth (encoding CSE) in mice exacerbated iron overload-induced cardiac hypertrophy, systolic dysfunction, and interstitial fibrosis. These effects correlated with reduced expression of the cysteine transporter SLC7A11, impaired glutathione (GSH) synthesis, and suppression of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4) antioxidant signaling pathway. Conversely, CSE overexpression in cardiomyocytes restored SLC7A11 stability, and suppressed reactive oxygen species (ROS) production through the Nrf2/HO-1/GPX4 pathway, thereby attenuating iron-mediated oxidative damage. Mechanistically, CSE deficiency disrupted both cysteine uptake via SLC7A11and cysteine production via transsulfuration pathway, inducing a self-reinforcing cycle of oxidative stress.
These findings demonstrate that the CSE-transsulfuration pathway serves as a crucial regulator of cysteine metabolism and antioxidant signaling in cardiomyocytes, presenting a potential therapeutic target in iron-induced cardiomyopathy.
Keywords:
Cardiac injury
Iron overload
cystathionine γ-lyase
cysteine
oxidative stress
SLC7A11
Nrf2
GPX4
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