Macrophage Notch1 drives hepatocyte ferroptosis via the exosomal miR-142a-3p/TIPE2 axis to promote MASH progression.

Authors

Xiaoyu Dong, Mengya Zhang, Xiaoxing Huang, Fan Guo, Qintong Hu, Yanxue Feng, Lanxuan Jiang, Qinyong Zhang, Yue Ge, Xin Song, Junke Zhao, Kun Li, Jie Ping

Published in

Cell & bioscience. Jul 12, 2026. Epub Jul 12, 2026.

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a serious chronic liver disease, in which ferroptosis has been identified as a crucial triggering event. However, the precise mechanisms of ferroptosis activation in MASH have not been fully disclosed. Herein, we found a positive association between macrophage Notch1 activation and hepatocyte ferroptosis in MASH patients and mice. Further, macrophage-specific Notch1 knockout (Notch1^M-KO) mice showed ameliorative MASH symptoms, including less liver injury, lipid accumulation, inflammation, and collagen deposition. These mice also exhibited reduced hepatocyte ferroptosis, evidenced by decreased Fe²⁺ levels and expression of pro-ferroptosis genes (Hamp and Ptgs2) and higher expression of anti-ferroptosis genes (Gpx4 and Slc7a11), as well as improved mitochondrial structure. Moreover, hepatocytes that received exosomes from Notch1-deficient macrophages exhibited decreased ferroptosis, while the tail vein infusion of Notch1-activated macrophage exosomes aggravated ferroptosis and MASH symptoms, identifying the role of macrophage Notch1-exosomes in promoting hepatocyte ferroptosis under MASH. Mechanistically, we discovered that macrophage Notch1 activation increased the level of exosomal miR-142a-3p by miRNA sequencing and decreased its target gene TIPE2, and confirmed that the inhibition of miR-142a-3p upregulated the Notch1 activation-induced TIPE2 decrease. Besides, overexpression of TIPE2 in hepatocytes inhibited ferroptosis. Collectively, our findings uncover a novel mechanism by which Notch1 activation in hepatic macrophages promotes hepatocyte ferroptosis through the exosomal miR-142a-3p/TIPE2 axis in MASH. We revealed a novel insight into hepatocyte ferroptosis activation from the perspective of macrophage, and discovered a pivotal role of macrophage Notch1 in hepatocyte ferroptosis during MASH progression, highlighting a potential therapeutic target for MASH treatment.

PMID:
42437940
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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