Inhibition of PERK signaling suppresses tumor progression and blocks GP73-GRP78-dependent stromal activation in hepatocellular carcinoma

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.