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The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing year by year and has become one of the leading causes of end-stage liver disease worldwide. Triggering Receptor Expressed on Myeloid Cells 2 (Trem2) has been confirmed to play an essential role in the progression of MASLD, but its specific mechanism still needs to be clarified. This study aims to explore the role and mechanism of Trem2 in MASLD. Human liver tissues were obtained from patients with MASLD and controls. Myeloid-specific knockout mice (Trem2mKO) and myeloid-specific overexpression mice (Trem2TdT) were fed a high-fat diet, either AMLN or CDAHFD, to establish the MASLD model. Relevant signaling molecules were assessed through lipidomics and RNA-seq analyses after that. Trem2 is upregulated in human MASLD/MASH-associated macrophages and is associated with hepatic steatosis and inflammation progression. Hepatic steatosis and inflammatory responses are exacerbated with the knockout of myeloid Trem2 in MASLD mice, while mice overexpressing Trem2 exhibit the opposite phenomenon. Mechanistically, Trem2mKO can aggravate macrophage pyroptosis through the PI3K/AKT signaling pathway and amplify the resulting inflammatory response. At the same time, Trem2 promotes the inflammation resolution phenotype transformation of macrophages through TGFβ1, thereby promoting tissue repair. Myeloid Trem2 ameliorates the progression of Metabolic dysfunction-associated steatotic liver disease by regulating macrophage pyroptosis and inflammation resolution. We believe targeting myeloid Trem2 could represent a potential avenue for treating MASLD. [Display omitted] • Trem2 is upregulated in human MASLD and associated with hepatic steatosis and inflammation. • Knockout of Trem2 exacerbated hepatic steatosis and inflammatory response in MASLD mice. • Trem2 can ameliorate MoMF pyroptosis by activating the PI3K/AKT signaling pathway. • Trem2 promotes the MoMF inflammation resolution phenotype transformation through TGFβ1. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming plays a crucial role in the development of hepatocellular carcinoma (HCC). However, the key drivers of metabolic reprogramming underlying HCC progression remain unclear. Using a large-scale transcriptomic database and survival correlation screening, we identify thymidine kinase 1 (TK1) as a key driver. The progression of HCC is robustly mitigated by TK1 knockdown and significantly aggravated by its overexpression. Furthermore, TK1 promotes the oncogenic phenotypes of HCC not only through its enzymatic activity and production of deoxythymidine monophosphate (dTMP) but also by promoting glycolysis via binding with protein arginine methyltransferase 1 (PRMT1). Mechanistically, TK1 directly binds PRMT1 and stabilizes it by interrupting its interactions with tripartite-motif-containing 48 (TRIM48), which inhibits its ubiquitination-mediated degradation. Subsequently, we validate the therapeutic capacity of hepatic TK1 knockdown in a chemically induced HCC mouse model. Therefore, targeting both the enzyme-dependent and -independent activity of TK1 may be therapeutically promising for HCC treatment. [Display omitted] • TK1 promotes HCC progression in enzyme-dependent and -independent manners • TK1 enhances glycolysis and glycolysis-related malignancy in HCC by upregulating PRMT1 • TK1 stabilizes PRMT1 by interrupting TRIM48-mediated ubiquitination degradation • Targeting TK1 impairs HCC progression in a chemically induced HCC mouse model Via a large-scale transcriptomic database and survival correlation screening, Li et al. report that TK1 contributes to HCC progression beyond its enzymatic activity and production of dTMP, through the enzyme-independent promotion of glycolysis via a direct interaction with PRMT1. Therefore, targeting TK1 may be therapeutically promising for HCC treatment. [ABSTRACT FROM AUTHOR]