MIF-mediated crosstalk between THRSP+ hepatocytes and CD74+ lipid-associated macrophages in hepatic periportal zone drives MASH

作者：Xu Xu, Hai-Liang Li, Hai Lin, Qing Li, Yuenan Liu, Weijun Huang, Jundong Yang, Na Li, Zhenfei Gao, Sheng-Ming Wang, Hangdong Shen, Wenjun Xue, Haolin Yuan, Wei Wang, Jianwei Shuai, Junli Liu, Shankai Yin, Feng Liu · 发表于：Hepatology · 年份：2025 · DOI：10.1097/hep.0000000000001429 · 被引用次数：12 · 研究领域：Macrophage Migration Inhibitory Factor、Liver physiology and pathology、Liver Disease Diagnosis and Treatment

BACKGROUND AND AIMS: Spatial location of steatosis is closely related to the progression of metabolic dysfunction-associated steatohepatitis (MASH), and reports suggest lipid-associated macrophages (LAMs) facilitate this progression. However, the underlying mechanisms remain elusive. APPROACH AND RESULTS: Spatial transcriptomics (ST) data revealed a significant increase in myeloid cells and MASH-related genes in the hepatic periportal (PP) zone of MASH mice, suggesting a vital role of the PP zone in MASH progression. THRSP (SPOT14), involved in fatty acid synthesis, was markedly elevated in the livers of MASH patients and mice. Notably, CellPhoneDB analysis identified strong interactions between CD74 and macrophage migration inhibitory factor (MIF) within the Thrsp -high zone. Furthermore, Thrsp , Cd74 , Mif , Col3a1 , and LAMs markers were prominently colocalized in the hepatic PP zone of MASH mice, suggesting that Thrsp -mediated crosstalk in this region played a crucial role in MASH progression. Thrsp overexpression/knockout experiments confirmed that THRSP drove MASH progression by recruiting CD74 + LAMs mediated by MIF. Mechanistically, THRSP promoted hepatic palmitic acid (PA) synthesis, mainly by promoting hepatic de novo lipogenesis, and disturbing the binding of FASN-TRIM21, thereby inhibiting FASN ubiquitination. CD74 + LAMs were activated and recruited by chemokine-like MIF secreted from hepatocytes and macrophages stimulated with PA. Additionally, the compound C6,...