Endoplasmic reticulum stress sensor protein PERK in hepatic stellate cells promotes the progression of hepatocellular carcinoma via p38d MAPK/IL-1ß axis
Palmitic acid (PA) absorption from the intestine is increased in metabolic dysfunction-associated steatohepatitis (MASH). It induces endoplasmic reticulum (ER) stress and interleukin-1 beta (IL-1ß) production in hepatic stellate cells (HSCs). Protein kinase R-like endoplasmic reticulum kinase (PERK) is an ER stress sensor protein involved in HSC activation and liver fibrosis. However, its role in HSCs during hepatocellular carcinoma (HCC) progression remains unclear. This study clarified the process of IL-1ß production via PERK in HSCs and explored the mechanism underlying MASH-related HCC progression. HSCs were treated with PA or transfected with PERK small-interfering RNA (siRNA) or PERK plasmid. Proliferation, scratch, and Transwell assays were performed on HCC cells cultured in the conditioned medium (CM) from HSCs. PA treatment increased PERK and IL-1ß expressions in HSCs. PERK knockdown decreased IL-1ß expression, while its overexpression increased it in HSCs. The CM from PA-treated HSCs showed elevated IL-1ß levels and enhanced HCC cells' proliferation, migration, and invasion; however, these effects were suppressed by PERK knockdown in HSCs. RNA-sequencing analysis revealed that p38d mitogen-activated protein kinase (MAPK) is the intermediate molecule between PERK and IL-1ß in HSCs. In the tumor microenvironment of MASH-related HCC, PERK in HSCs promotes HCC progression via the p38d MAPK/IL-1ß axis. Overall design: RNA-seq profiling of LX-2 cells transfected with control or PERK siRNA and then treated with palmitic acid