NOX4/Keap1/Nrf2/ROS signaling drives ferroptosis in trimethyltin chloride-induced cardiac developmental malformations

Jan 4, 2026Toxicology

How cellular stress signals cause iron-related cell death in heart defects from trimethyltin chloride exposure

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Exposure to Trimethyltin chloride (TMT) induces cardiac malformations in zebrafish embryos.

TMT exposure leads to cardiac malformations, pericardial edema, and reduced heart rate in zebrafish embryos.
TMT increases the expression of nox4 in embryonic hearts, which plays a significant role in generating reactive oxygen species (ROS).
Inhibition or genetic knockdown of nox4 significantly reduces TMT-induced cardiac defects.
Suppression of nox4 interferes with the dysregulation of the Keap1/Nrf2 pathway and prevents excessive ROS accumulation and mitochondrial damage.
Ferroptosis-specific inhibitors confirm that ferroptosis is directly involved in TMT-induced cardiac developmental defects.

AI simplified

Trimethyltin chloride (TMT), a pervasive environmental organic tin pollutant, has been implicated in cardiac injury, though its underlying mechanisms remain unclear. TMT exposure triggers excessive reactive oxygen species (ROS) generation, a key inducer of ferroptosis-a regulated form of cell death driven by iron-dependent lipid peroxidation. NADPH oxidase 4 (NOX4), highly expressed during cardiac development, plays a critical role in myocardial ROS production, while the Keap1/Nrf2 pathway regulates cellular ROS homeostasis. We hypothesized that TMT induces cardiac developmental defects by activating NOX4/Keap1/ROS-mediated ferroptosis. TMT exposure induced cardiac malformations, pericardial edema, and reduced heart rate in zebrafish embryos. Further studies revealed that TMT upregulated nox4 expression in embryonic hearts. Notably, pharmacological inhibition or genetic knockdown of nox4 markedly attenuated TMT-induced cardiac defects. Moreover, nox4 suppression antagonized TMT-triggered dysregulation of the Keap1/Nrf2 axis, ROS overaccumulation, mitochondrial damage, and ferroptosis-related abnormalities-including Fe²⁺ accumulation, elevated lipid peroxidation, and downregulated glutathione peroxidase 4 (GPX4) expression. Crucially, inhibition or knockdown of keap1 similarly mitigated TMT-induced ROS bursts, mitochondrial injury, and ferroptosis progression. Intervention with ferroptosis-specific inhibitors (Liproxstatin-1 and Myricetin) confirmed that ferroptosis directly contributes to TMT-induced cardiac developmental defects. This study demonstrates that TMT induces cardiac malformations by activating ferroptosis via the nox4/Keap1/Nrf2/ROS signaling axis. These findings reveal a novel mechanism underlying TMT cardiotoxicity, provide theoretical insights for assessing TMT exposure as a risk factor for congenital heart disease, and identify potential molecular targets for therapeutic intervention.

Full Text

Full text is available at the source.

View full text (XML) ↗View full text ↗

NOX4/Keap1/Nrf2/ROS signaling drives ferroptosis in trimethyltin chloride-induced cardiac developmental malformations

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief