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Adaptación hepática al estrés metabólico crónico primes tumorigénesis

Constantine N Tzouanas¹, Jessica E S Shay², Marc S Sherman³

¹Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.

|December 23, 2025

Resumen

El estrés crónico altera las células del hígado que sobreviven, activando programas de desarrollo y cáncer mientras reduce la función. Estos cambios celulares, impulsados por reguladores específicos, pueden impulsar la futura tumorigénesis del hígado y la enfermedad.

Área de la Ciencia:

Biología celular
Biología molecular
Investigación sobre el cáncer

Sus antecedentes:

El estrés crónico afecta la función celular y la supervivencia, particularmente en los hepatocitos responsables de las funciones metabólicas y de desintoxicación vitales.
La esteatohepatitis asociada a la disfunción metabólica (MASH) puede surgir de desequilibrios crónicos de nutrientes que conducen a la muerte de los hepatocitos.
Investigaciones anteriores identificaron factores de muerte de los hepatocitos inducidos por el estrés, pero los efectos en las células sobrevivientes no estaban claros.

Objetivo del estudio:

Investigar el impacto funcional del estrés crónico en los hepatocitos no transformados.
Identificar los mecanismos moleculares y los reguladores que impulsan los cambios celulares bajo estrés crónico.
Explorar el vínculo entre las respuestas al estrés crónico en los hepatocitos y la futura tumorigénesis.

Principales métodos:

Análisis multiómico longitudinal de una sola célula entre especies.
Desarrollo y aplicación de métodos computacionales integradores.
Validación experimental de los reguladores maestros identificados.
Regresión geográfica en el tejido humano microarray transcriptómica espacial.

Principales resultados:

El estrés continuo promueve el pronóstico del desarrollo y los programas asociados al cáncer en los hepatocitos.
La identidad funcional de los hepatocitos maduros se reduce en condiciones de estrés crónico.
Los reguladores maestros identificados alteran el equilibrio hepatocitario, aumentan la proliferación y la tumorigénesis primaria.
Las comunidades multicelulares estructuradas espacialmente y las interacciones de señalización influyen en las respuestas al estrés.

Conclusiones:

El estrés crónico reprograma fundamentalmente los hepatocitos sobrevivientes, desplazándolos hacia estados proliferativos y potencialmente oncogénicos.
Las adaptaciones celulares tempranas al estrés crónico pueden sentar las bases para la tumorigénesis futura y los resultados adversos para la salud.
Los principales mecanismos de acción subyacen a diversas disfunciones celulares observadas en respuesta al estrés crónico.

Palabras clave:

Respuesta al estrés crónico desarrollo de métodos computacionales Primado epigenético perturbación genética el hígado el metabolismo genómica de una sola célula memoria de tejido

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