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Inhibition of PERK signaling suppresses tumor progression and blocks GP73-GRP78-dependent stromal activation in hepatocellular carcinoma
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DOI：10.1016/j.neo.2026.101329.png)
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Abstract
En 中文
Endoplasmic reticulum (ER) stress contributes to hepatocellular carcinoma (HCC) progression and promotes the development of a pro-tumorigenic microenvironment. Here, we demonstrate that selective inhibition of the ER-stress sensor PERK using AMG-PERK substantially restrains tumor development when administered during early carcinogenesis in a chemically induced HCC model. PERK inhibition reduced tumor burden, proliferation, and cell viability in vivo, and impaired the growth of HCC cells and patient-derived organoids in vitro. In parallel, AMG-PERK markedly reduced stromal activation, fibrosis, and inflammatory signaling within the tumor microenvironment. Mechanistic analyses indicated that ER-stress enhances tumor-stromal communication in part through increased secretion of the glycoprotein GP73, which can activate hepatic stellate cells via GRP78-dependent signaling. Blocking PERK or using GRP78-targeting antibodies reduced stellate cell activation and fibrogenic responses. Single-cell RNA sequencing and patient biopsies showed that PERK/EIF2AK3 and GP73/GOLM1 are upregulated in malignant hepatocytes and associated with poor clinical outcomes. Transcriptomic profiling further revealed that ER-stress drives oncogenic programs, including MYC signaling, epithelial-to-mesenchymal transition, and inflammatory pathway activation, all of which were affected by pharmacological PERK inhibition. Together, these findings identify PERK signaling as a potential driver of malignant progression and microenvironmental remodeling in HCC and establish PERK inhibition as a promising therapeutic strategy to target both tumor cells and their stromal interactions during the initial stages of hepatocarcinogenesis.
Keywords:
Hepatocellular carcinoma
Endoplasmic reticulum stress
PERK pathway
GP73
Tumor-stromal interactions
AFP
alpha-fetoprotein
αSMA
alpha smooth muscle actin
ATF6
activating transcription factor 6
BP
biological process
CAFs
cancer-associated fibroblasts
CTGF
connective tissue growth factor
DEN
N-nitrosodiethylamine
EMT
epithelial-mesenchymal transition
ER
endoplasmic reticulum
FPKM
fragments per kilobase of exon per million reads mapped
GEO
gene expression omnibus
GO
gene ontology
GOLM1
Golgi membrane protein 1
GP73
Golgi protein 73
GRP78
glucose-regulated protein 78
GSEA
gene set enrichment analysis
HCC
hepatocellular carcinoma
HSCs
hepatic stellate cells
IL-6
interleukin 6
IRE1α
inositol-requiring enzyme 1α
KEGG
Kyoto encyclopedia of genes and genomes
LsPERK-KO
PERK knockout mice
MASLD
metabolic dysfunction-associated steatotic liver disease
MMPs
matrix metalloproteinases
PERK
protein kinase RNA-like ER kinase
scRNA-seq
single-cell RNA sequencing
TACE
transarterial chemoembolization
TAM
tumor-associated macrophages
TCGA
the cancer genome atlas
TECs
tumor endothelial cells
TGF-β
transforming growth factor beta
Thapsi
Thapsigargin
TM
tumor-conditioned medium
TME
tumor microenvironment
TNF-α
tumor necrosis factor alpha
t-SNE
t-distributed stochastic neighbor embedding
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