Morita Makoto, Tokumoto Yoshio, Watanabe Takao, Imai Yusuke, Yukimoto Atsushi, Shimamoto Toyoki, Yano Ryo, Okazaki Yuki, Nakamura Yoshiko, Yoshida Osamu, Miyake Teruki, Hirooka Masashi, Abe Masanori, Hiasa Yoichi
Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan.
Sci Rep. 2025 Jun 6;15(1):20030. doi: 10.1038/s41598-025-04150-w.
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-1β) 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-1β 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-1β expression in HSCs. PERK knockdown decreased IL-1β expression, while its overexpression increased it in HSCs. The CM from PA-treated HSCs showed elevated IL-1β levels and enhanced HCC cells' proliferation, migration, and invasion; however, these effects were suppressed by PERK knockdown in HSCs. RNA-sequencing analysis revealed that p38δ mitogen-activated protein kinase (MAPK) is the intermediate molecule between PERK and IL-1β in HSCs. In the tumor microenvironment of MASH-related HCC, PERK in HSCs promotes HCC progression via the p38δ MAPK/IL-1β axis.
在代谢功能障碍相关脂肪性肝炎（MASH）中，肠道对棕榈酸（PA）的吸收增加。它可诱导肝星状细胞（HSC）内质网（ER）应激和白细胞介素-1β（IL-1β）的产生。蛋白激酶R样内质网激酶（PERK）是一种参与HSC激活和肝纤维化的ER应激传感蛋白。然而，其在肝细胞癌（HCC）进展过程中在HSC中的作用仍不清楚。本研究阐明了HSC中通过PERK产生IL-1β的过程，并探讨了MASH相关HCC进展的潜在机制。用PA处理HSC或用PERK小干扰RNA（siRNA）或PERK质粒转染HSC。对在HSC条件培养基（CM）中培养的HCC细胞进行增殖、划痕和Transwell试验。PA处理增加了HSC中PERK和IL-1β的表达。PERK敲低降低了IL-1β的表达，而其过表达则增加了HSC中IL-1β的表达。PA处理的HSC的CM显示IL-1β水平升高，HCC细胞的增殖、迁移和侵袭增强；然而，HSC中的PERK敲低抑制了这些作用。RNA测序分析表明，p38δ丝裂原活化蛋白激酶（MAPK）是HSC中PERK和IL-1β之间的中间分子。在MASH相关HCC的肿瘤微环境中，HSC中的PERK通过p38δ MAPK/IL-1β轴促进HCC进展。
