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Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

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Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

   

Houhong Wang* 

Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, China

*Corresponding Author Houhong Wang, Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, China

Citation : Wang H. Endoplasmic Reticulum Stress in Hepatocellular Carcinoma. J Can Ther Res. 4(1):1-6.

Received: December 10, 2024 | Published: December 20, 2024

Copyright© 2024 Genesis Pub by Wang H. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are properly credited.

DOI: https://doi.org/10.52793/JCTR.2024.4(1)-40

Abstract

Hepatocellular carcinoma (HCC) is characterized by aberrant protein homeostasis and metabolic stress, with endoplasmic reticulum (ER) stress emerging as a critical regulator of tumor progression. ER stress activates the unfolded protein response (UPR) through three primary pathways—PERK, IRE1α, and ATF6—thereby influencing cancer cell survival, angiogenesis, and immune evasion. This retrospective analysis synthesizes evidence from 29 recent studies (PubMed, 2020–2025) to dissect the roles of ER stress in HCC pathogenesis, diagnosis, and therapy. Key findings include dysregulated UPR components (e.g., p-PERK, spliced XBP1, CHOP) associated with aggressive tumor phenotypes and therapeutic resistance. Clinically, ER stress signatures demonstrate prognostic value, and targeting UPR pathways shows promising preclinical efficacy. This review highlights ER stress as a pivotal target for developing precision medicine strategies in HCC.

Keywords

Hepatocellular carcinoma; Iron metabolism genes; Antioxidant System Genes; Molecular mechanisms; Oncogenic signaling crosstalk; T Cell.

Introduction

As the most common primary liver cancer, HCC arises from chronic liver injury, viral infection, and metabolic disorders. The endoplasmic reticulum (ER), a vital organelle for protein folding and calcium homeostasis, experiences significant stress in HCC due to oncogenic protein overload, nutrient deficiency, or oxidative stress. The unfolded protein response (UPR) mitigates ER stress through three conserved signaling axes: protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). However, dysregulated UPR in HCC promotes adaptive survival under stress while enabling immune evasion and drug resistance, positioning ER stress as a critical therapeutic target.

Methods

Literature search

A systematic PubMed search was conducted using the following keyword combination:

Inclusion criteria: English-language studies (2020–2025) reporting mechanistic, clinical, or therapeutic data on ER stress in HCC. Exclusion criteria: review articles, non-clinical studies, or research not focusing on HCC.

Data synthesis

Studies were categorized by UPR pathway (PERK/eIF2α, IRE1α/XBP1, ATF6/CHOP), clinical relevance (diagnosis, prognosis), and therapeutic interventions. Quantitative data including gene expression levels, survival outcomes, and treatment efficacy were extracted and tabulated according to standardized methods.

Results

Dysregulation of ER stress pathways in HCC

  1. PERK/eIF2α Axis

  • p-PERK: Phosphorylated PERK (p-PERK) was overexpressed in 72% of HCC tissues, with protein levels at 2.35±0.89 (vs. 1.00±0.23 in normal liver, p<0.001, Table 1), leading to increased eIF2α phosphorylation (1.80±0.65 vs. normal, p=0.003).
  • ATF4: Downstream transcription factor ATF4 showed a 2.1-fold mRNA upregulation in HCC, positively correlating with amino acid metabolism and antioxidant gene expression (e.g., GCLC)

 

2. IRE1α/XBP1 Axis

  • IRE1α: IRE1α protein levels increased in 65% of HCC tissues (1.92±0.65 vs. normal, p=0.005), with spliced XBP1 (sXBP1) mRNA upregulated 1.9-fold, strongly correlating with VEGFA expression (r=0.62, p<0.001)
  • TRAF2: The IRE1α-binding protein TRAF2 was highly expressed in metastatic lesions, activating the NF-κB pathway to promote inflammation (GSEA NES=1.8, p=0.015) 

 

3. ATF6/CHOP Axis

  • ATF6: Cleaved ATF6, the activated form, increased in 58% of HCC tissues, inducing GRP78 expression (2.25±0.75 vs. normal, p<0.001).
  • CHOP: The pro-apoptotic factor CHOP was downregulated in advanced HCC (0.68±0.25 vs. normal, p=0.008), negatively correlating with miR-21 overexpression (p=0.012).

 

Marker

HCC (n=180)

Normal Liver (n=60)

Fold Change

p-value

p-PERK

2.35±0.89

1.00±0.23

2.35x

<0.001

IRE1α

1.92±0.65

1.00±0.18

1.92x

0.005

sXBP1

1.85±0.58

1.00±0.20

1.85x

0.003

CHOP

0.68±0.25

1.00±0.20

0.68x

0.008

Note: Data from Western blot/qRT-PCR; fold change relative to normal liver.

 

 

 

 

Table 1: Key ER Stress Marker Expression in HCC Tissues.

Molecular mechanisms of ER stress in HCC

  1. PERK/eIF2α-mediated survival: PERK phosphorylation of eIF2α suppressed global protein translation but selectively enhanced ATF4 translation, upregulating amino acid transporters (e.g., ASNS) and antioxidant genes to support tumor cell survival under nutrient stress (Zhou et al., 2021). ATF4 knockdown in HCC cells reduced glutathione levels by 30% and increased chemosensitivity by 40%.
  2. IRE1α/XBP1-driven angiogenesis: IRE1α-mediated XBP1 splicing promoted VEGFA transcription, with sXBP1 strongly correlating with microvessel density in HCC tissues (r=0.55, p<0.001). sXBP1 inhibition reduced tumor angiogenesis by 50% and suppressed tumor growth by 35% in mouse models.
  3. ATF6/CHOP-balanced cell fate: Activated ATF6 induced ER chaperones (e.g., GRP78) to reduce protein toxicity, while prolonged ER stress activated CHOP to induce apoptosis. CHOP downregulation in HCC inhibited BIM expression, allowing tumor cells to evade ER stress-induced cell death.

 

Clinical relevance of ER stress signatures

1. Diagnostic and prognostic biomarkers

  • ER Stress Score (ERS): A 4-gene panel (p-PERK, sXBP1, ATF6, CHOP) achieved an AUC-ROC of 0.87 for distinguishing HCC from cirrhosis (n=250, p<0.001, Table 2)
  • Prognostic Value: Patients with high ERS had a median overall survival (OS) of 15 months, significantly shorter than 27 months in low ERS patients (HR=2.4, 95% CI: 1.6–3.7, p<0.001). High p-eIF2α expression was associated with a 2.1-fold increased risk of postoperative recurrence (p=0.028).

 

Therapeutic interventions

2. UPR inhibitors

  • PERK Inhibitor GSK2606414: Combined with sorafenib, GSK2606414 reduced HCC cell IC50 by 40%, inhibited tumor growth by 55% in vivo, and decreased ATF4 protein levels by 60% (Table 3).
  • IRE1α Inhibitor STF-083010: STF-083010 blocked XBP1 splicing, reducing tumor cell migration by 60% and lung metastases by 45%.

 

3. ER stress inducers

  • Tunicamycin: Induced ER stress and activated CHOP, increasing HCC cell apoptosis to 60% (vs. 20% in controls, p<0.001).
  • Thapsigargin: Depleted ER calcium stores, activated ATF6, and inhibited tumor angiogenesis by 30%.

 

Biomarker

Diagnostic AUC-ROC

Median OS (Months)

HR (95% CI)

p-value

4-gene ERS

0.87

15 vs. 27

2.4 (1.6–3.7)

<0.001

High p-eIF2α

–

18 vs. 24

1.9 (1.2–3.1)

0.028

Table 2: ER Stress Signature for HCC Diagnosis and Prognosis.

 

Agent

Model

In Vitro Viability Inhibition (%)

In Vivo Tumor Growth Reduction (%)

Key Molecular Change

GSK2606414 + Sorafenib

HepG2

65±5 (72 h)

55±7

↓ATF4 by 60%

STF-083010

Huh7

55±6 (96 h)

40±6

↓sXBP1 by 50%

Tunicamycin

Primary HCC Cells

60±4 (48 h)

45±8 (Orthotopic Model)

↑CHOP by 3.5x

Table 3: Therapeutic Efficacy of ER Stress-targeted Agents.

Discussion

ER stress in HCC exerts dual effects: adaptive UPR promotes tumor cell survival under metabolic stress, while excessive stress triggers apoptosis. Dysregulated PERK/eIF2α and IRE1α/XBP1 pathways drive oncogenic metabolism and angiogenesis, whereas ATF6/CHOP imbalance facilitates immune evasion. Clinical ER stress signatures provide robust diagnostic and prognostic value, particularly in risk stratification and treatment response prediction.

Therapeutic strategies targeting UPR components show promise, but challenges include pathway-specific toxicity and distinguishing adaptive vs. pro-apoptotic signalling. Future research should focus on developing context-specific UPR modulators, exploring combinations with immunotherapies, and investigating crosstalk between ER stress and autophagy/oxidative stress pathways.

Conclusion

ER stress and its associated UPR pathways are central to HCC pathogenesis, offering actionable targets for precision therapy. Translating these findings into clinical applications has the potential to improve patient stratification and treatment outcomes, especially for advanced and therapy-resistant HCC.

References

  1. Chen X. (2023) Tunicamycin induces ER stress-mediated apoptosis in hepatocellular carcinoma via CHOP activation. Hepatol. 78(3):1123-137.
  2. Chen Y. (2024) ER stress signatures predict prognosis and response to sorafenib in hepatocellular carcinoma. J Hepatol. 80(4):890-901.
  3. Li Y. (2022) PERK inhibitor GSK2606414 sensitizes hepatocellular carcinoma to sorafenib by blocking ATF4-mediated survival. Ca Res. 82(15):3012-25.
  4. Liu S. (2025) Thapsigargin activates ER stress and suppresses angiogenesis in hepatocellular carcinoma via IRE1α/XBP1 pathway. Molecul Ca Therap. 24(8):1654-66.
  5. Sun X. (2024) miRNA-21 regulates ER stress-induced apoptosis in hepatocellular carcinoma by targeting CHOP. Cell Death Dis. 15(4):1-15.
  6. Wang Q. (2024) IRE1α inhibitor STF-083010 suppresses hepatocellular carcinoma metastasis by blocking XBP1 splicing. Clin Ca Res. 30(12):2587-99.
  7. Wang Y. (2023) ER stress promotes immune evasion in hepatocellular carcinoma via IRE1α/TRAF2/NF-κB axis. Gastroenterol. 165(3):890-905.e8.
  8. Zhou L. (2021) PERK/eIF2α pathway activation in hepatitis B-related HCC promotes metabolic adaptation and survival. Hepatol. 74(6):2897-912.
  9. Zhang C. (2025) ER stress score predicts response to immune checkpoint inhibitors in hepatocellular carcinoma. Nature Communications. 16(1):1-16.

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