Downregulation of 15-PGDH enhances MASH-HCC development via fatty acid-induced T-cell exhaustion
Xichen Hu, Tadahito Yasuda, Noriko Yasuda-Yosihara, Atsuko Yonemura, Terumasa Umemoto, Yutaka Nakachi, Kohei Yamashita, Takashi Semba, Kota Arima, Tomoyuki Uchihara, Akiho Nishimura, Luke Bu, Lingfeng Fu, Feng Wei, Jun Zhang, Yilin Tong, Huaitao Wang, Kazuya Iwamoto, Takaichi Fukuda, Hayato Nakagawa, Koji Taniguchi, Yuji Miyamoto, Hideo Baba, Takatsugu Ishimoto
Abstract
Background and AimsHepatocellular carcinoma (HCC) mainly develops from chronic hepatitis. Metabolic dysfunction-associated steatohepatitis (MASH) has gradually become the main pathogenic factor for HCC due to the rising incidence of obesity and metabolic diseases. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the enzyme that degrades prostaglandin 2 (PGE2), which is known to exacerbate inflammatory responses. However, the role of PGE2 accumulation caused by 15-PGDH downregulation in the development of MASH-HCC has not been determined.MethodsWe utilized the steric animal model (STAM) to establish a MASH-HCC model using WT and 15-Pgdh+/− mice to assess the significance of PGE2 accumulation in MASH-HCC development. Additionally, we analyzed clinical samples obtained from MASH-HCC patients.ResultsWe showed that PGE2 accumulation in the tumor microenvironment (TME) induced ROS production in macrophages and the expression of cell growth-related genes and antiapoptotic genes. On the other hand, the downregulation of fatty acid metabolism in the background liver promoted lipid accumulation in the TME, causing a decrease in mitochondrial membrane potential and CD8+ T-cell exhaustion, which led to enhanced MASH-HCC development.Conclusions15-PGDH downregulation inactivates immune surveillance by promoting the proliferation of exhausted effector T cells, which enhances hepatocyte survival and proliferation and leads to MASH-HCC development.