Related Experiment Video

Updated: Aug 6, 2026

Revealing the Ferroptotic Phenotype of Medulloblastoma
04:01

Revealing the Ferroptotic Phenotype of Medulloblastoma

Published on: March 15, 2024

Targeting the 4EBP1/HSP90β/Nrf2 Axis Sensitizes β-catenin-mutant Hepatocellular Carcinoma to mTOR Inhibitors via

Rong Li1, Yi Zhou2, Zimu Wang3

  • 1Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Journal of Clinical and Translational Hepatology
|July 22, 2026
PubMed
Abstract

Insights

This study reveals how 4EBP1A4 enhances Nrf2 degradation, overcoming mTOR-mediated ferroptosis suppression and improving rapamycin efficacy in hepatocellular carcinoma (HCC). Combination therapy with mTOR and ERK inhibitors shows potent tumor suppression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Aberrant mTOR pathway activation drives hepatocellular carcinoma (HCC) progression.
  • mTOR-mediated ferroptosis suppression contributes to HCC chemoresistance.
  • Understanding mTOR inhibitor resistance mechanisms is crucial for effective HCC treatment.

Purpose of the Study:

  • Elucidate mechanisms of mTOR inhibitor resistance in HCC.
  • Evaluate therapeutic potential of multidrug combinations in β-catenin-mutant HCC.
  • Investigate the role of 4EBP1 in ferroptosis regulation and drug sensitivity.

Main Methods:

  • Cell transfection with 4EBP1 and HSP90β plasmids, followed by rapamycin treatment.
  • Western blotting, co-immunoprecipitation, and immunofluorescence to study 4EBP1 function.
  • In vivo evaluation of mTOR and ERK inhibitors, alone and in combination, in HCC mouse models.

Main Results:

  • 4EBP1A4 promoted ferroptosis and enhanced rapamycin efficacy by increasing Keap1-Nrf2 complex formation and Nrf2 degradation via the HSP90β/Keap1 axis.
  • Rapamycin, MLN0128, and PD901 induced ferroptosis and inhibited HCC cell proliferation.
  • Combination therapy demonstrated the strongest tumor suppressive effect.

Conclusions:

  • 4EBP1A4 overcomes mTOR-mediated ferroptosis suppression and synergizes with rapamycin.
  • mTOR and ERK inhibitors, particularly in combination, represent a potent therapeutic strategy for HCC by inducing ferroptosis.
  • Targeting the HSP90β/Keap1/Nrf2 axis offers a novel approach to enhance HCC treatment efficacy.
Keywords:
4EBP1Drug combinationFerroptosisHCCHepatocellular carcinomamTOR pathway

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...