This study identifies the SLC11A1-Sp1-GPX4 axis as a pivotal transcriptional regulator pathway driving ferroptosis in AMI, highlighting SLC11A1 as a promising therapeutic target.
Key Findings
Results
SLC11A1 expression was elevated in AMI conditions both in vitro and in vivo.
SLC11A1 expression was upregulated in hypoxia/reoxygenation (H/R)-treated H9c2 cardiomyocytes.
SLC11A1 expression was elevated in infarcted murine hearts in the in vivo AMI model.
SLC11A1 was identified as a differentially expressed gene through transcriptomic dataset analysis comparing AMI patients and healthy controls.
The gene belongs to the solute carrier family 11 member 1 and was identified via bioinformatic analysis of transcriptomic datasets.
Results
SLC11A1 silencing reduced infarct size and improved cardiac function in the murine AMI model.
SLC11A1 knockdown was validated in vivo using a murine AMI model.
Silencing of SLC11A1 led to a reduction in infarct size.
Cardiac function was improved following SLC11A1 silencing.
These effects were observed alongside suppression of ferroptosis markers.
Results
SLC11A1 silencing suppressed ferroptosis in cardiomyocytes.
Ferroptosis was suppressed in H/R-treated H9c2 cardiomyocytes upon SLC11A1 knockdown.
Ferroptosis suppression was also observed in the murine AMI model following SLC11A1 silencing.
Ferroptosis is described as a critical contributor to cardiomyocyte injury in AMI.
The ferroptosis-suppressive effect was mechanistically linked to changes in GPX4 expression.
Results
SLC11A1 mechanistically drives ferroptosis through transcriptional suppression of GPX4 mediated by the transcription factor Sp1.
SLC11A1 led to transcriptional suppression of glutathione peroxidase 4 (GPX4).
This suppression was mediated by the transcription factor specificity protein 1 (Sp1).
The mechanistic pathway was designated the SLC11A1-Sp1-GPX4 axis.
GPX4 is a key antioxidant enzyme whose suppression is associated with ferroptotic cell death.
The relationship was elucidated using both the in vitro H/R model and the in vivo murine AMI model.
Methods
Bioinformatic analysis of transcriptomic datasets from AMI patients identified SLC11A1 as a key ferroptosis-associated differentially expressed gene.
Transcriptomic datasets from AMI patients and healthy controls were analyzed.
Differentially expressed genes (DEGs) were identified through this comparison.
SLC11A1 was selected among DEGs for its association with ferroptosis.
Findings from bioinformatic analysis were subsequently validated experimentally in vitro and in vivo.
What This Means
This research suggests that a protein called SLC11A1 plays an important role in a type of cell death called ferroptosis, which contribuys to heart muscle damage during a heart attack (acute myocardial infarction, or AMI). The researchers found that SLC11A1 levels are abnormally high in heart cells deprived of oxygen and in mouse hearts after a heart attack. When they experimentally reduced SLC11A1 levels, the area of heart damage shrank and heart function improved, while this form of cell death was also reduced.
The study further uncovered the mechanism behind this effect: SLC11A1 acts through a chain of molecular events involving a regulatory protein called Sp1, which in turn suppresses a protective enzyme called GPX4. GPX4 normally helps prevent ferroptosis by neutralizing harmful molecules, so when SLC11A1 is high, GPX4 gets turned down and cells become more vulnerable to this type of death. This chain is referred to as the SLC11A1-Sp1-GPX4 axis.
This research suggests that SLC11A1 could be a target for new treatments aimed at reducing heart muscle damage during a heart attack. By blocking SLC11A1 or restoring GPX4 activity, it may be possible to protect heart cells from ferroptosis. These findings are based on lab cell experiments and mouse models, and further research would be needed before these insights could be translated into clinical therapies for humans.
Zhang S, Wang Y, Feng Y, Wang F, Zhu J. (2026). SLC11A1 Drives Ferroptosis in Acute Myocardial Infarction Via Sp1-mediated Transcriptional Repression of GPX4.. Journal of cardiovascular translational research. https://doi.org/10.1007/s12265-026-10782-8