Kenji Fukumoto, Hayato Hikita, Yoshinobu Saito, Yuki Makino, Kazumasa Soma, Seiya Kato, Yōichi Sasaki, Yuta Myojin, Katsuhiko Sato, Sadatsugu Sakane, Kazuhiro Murai, Yuki Tahata, Takahiro Kodama, Tomohide Tatsumi, Daisuke Motooka, Yoshiaki Kubota, Shogo Kobayashi, Hidetoshi Eguchi, Tetsuo Takehara
BACKGROUND & AIMS: Interleukin (IL)-1β is a key cytokine in hepatitis-related inflammation, but its role in metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH) remains unclear. This study investigated IL-1β-mediated interactions in nonparenchymal liver cells to elucidate their contributions to pathological MASH progression. METHODS: ) mice were subjected to a Western diet (WD) to establish a MASH model. An additional WD-fed cohort received the IL1R1 antagonist anakinra during the final 4 weeks. RNA sequencing data from liver tissues from patients with MASLD and spatial transcriptomic analyses focusing on nontumor regions of MASH-related hepatocellular carcinoma samples were evaluated. RESULTS: mice, WD-induced inflammatory cell infiltration and fibrosis were attenuated, and anakinra produced similar effects. In human datasets, CCL2 and CXCL10 were upregulated in MASH livers and correlated with NAFLD activity scores. Spatial transcriptomics revealed a dominant periportal macrophage-to-LSEC IL1B-IL1R1 interaction that generates chemokine-enriched LSECs, forming inflammatory-fibrotic niches that facilitate immune cell recruitment. CONCLUSIONS: Macrophage-derived IL-1β promotes hepatic inflammation and fibrosis through IL1R1-dependent chemokine induction in LSECs, highlighting IL1R1 signaling as a therapeutic target in MASH.