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

Background & 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 underling mechanisms remain elusive. Approach & Results: Spatial transcriptomics (ST) data revealed a significant increase in myeloid cells and MASH-related genes in hepatic periportal (PP) zone of MASH mice, suggesting a vital role of 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 co-localized in hepatic PP zone of MASH mice, suggesting that Thrsp -mediated crosstalk in this region played 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 identified as a THRSP inhibitor, significantly ameliorated MASH in mice. Conclusions: Our study demonstrates that THRSP drives MASH progression by recruiting CD74 + LAMs mediated by MIF in hepatic PP zone, providing novel insights into the spatial zonation and crosstalk between lipogenic hepatocytes and LAMs that may result in novel therapies for MASH.