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NFE2L2 protege contra la ferroptosis inducida por Sorafenib y la cardiotoxicidad mediante la activación de la vía

Hui Jiang¹, Yan Su², Yinglong Hou³

¹Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China; Department of Pediatrics, The Second Hospital of Shandong University, Jinan, Shandong 250012, China.

Toxicology and applied pharmacology

|August 30, 2025

Resumen

El factor de transcripción NFE2L2 protege contra la cardiotoxicidad inducida por Sorafenib mediante la activación de la vía HO-1/ ferritina, ofreciendo una nueva estrategia terapéutica para mitigar la lesión cardíaca inducida por el fármaco.

Área de la Ciencia:

Cardiología
Biología molecular
Farmacología

Sus antecedentes:

Sorafenib es un tratamiento eficaz contra el cáncer, pero causa cardiotoxicidad.
NFE2L2, un factor de transcripción, regula el estrés celular y el equilibrio del hierro.
La ferroptosis, una vía de muerte celular, está implicada en la lesión cardíaca inducida por drogas.

Objetivo del estudio:

Investigar el papel de NFE2L2 en la cardiotoxicidad inducida por Sorafenib.
Para aclarar los mecanismos moleculares subyacentes a los efectos protectores de NFE2L2.
Explorar estrategias terapéuticas dirigidas a NFE2L2 para un tratamiento más seguro con Sorafenib.

Principales métodos:

Se investigó la expresión de NFE2L2 en cardiomiocitos tratados con Sorafenib.
Utilizó inhibidores de la ferroposis (Fer-1, DFO) y agonistas knockdown/NFE2L2 (SFN).
Peroxidación lipídica analizada, especies reactivas del oxígeno (ROS) y eje HO-1/ferritina.
Las vías de activación NFE2L2 examinadas (estrés ER, EIF2AK3).
Eficacia de SFN evaluada in vivo para la cardiotoxicidad inducida por Sorafenib.

Principales resultados:

El sorafenib aumenta la expresión de NFE2L2 en los cardiomiocitos, relacionado con la ferroptosis.
La reducción de NFE2L2 exacerba la ferroptosis inducida por Sorafenib (aumento de la peroxidación lipídica, ROS).
NFE2L2 activa el eje HO-1/ferritina, aliviando el estrés oxidativo y promoviendo la homeostasis del hierro.
El sorafenib activa el NFE2L2 a través del estrés ER (EIF2AK3), no a través de la vía KEAP1.
El tratamiento con SFN mitigó la ferroptosis inducida por Sorafenib y la cardiotoxicidad in vivo.

Conclusiones:

NFE2L2 juega un papel protector crucial contra la cardiotoxicidad inducida por Sorafenib.
El eje NFE2L2-HO-1/ferritina es un mecanismo clave para mitigar la ferroptosis y el estrés oxidativo.
La activación de NFE2L2 dependiente del estrés de ER ofrece un nuevo objetivo terapéutico.
Los agonistas NFE2L2 como el SFN representan una estrategia prometedora para mejorar la seguridad de Sorafenib.

Palabras clave:

Cardiotoxicidad inducida por drogas Ferritina y sus derivados La ferroposis HO-1 y sus derivados NFE2L2 y NFE2L2 El Sorafenib

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