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Phenylalanine Reprograms TLS Maturation and Plasma cell differentiation in MASH-HCC [Spatial Transcriptomics]

ABSTRACT: Metabolic dysfunction–associated steatohepatitis (MASH) is a rapidly growing cause of hepatocellular carcinoma (HCC) and is associated with poor clinical outcomes and limited responsiveness to immune checkpoint inhibitors. Emerging evidence suggests that immune dysregulation within the tumor microenvironment contributes to disease progression; however, the transcriptional programs distinguishing MASH-associated HCC from non-MASH HCC remain incompletely characterized. To address this gap, we performed bulk RNA sequencing on total RNA isolated from MASH and non-MASH tumor tissues. This dataset was generated to enable comparative transcriptomic analysis of tumor-intrinsic and immune-related pathways associated with MASH-driven hepatocarcinogenesis, with particular relevance to immune organization, metabolic stress responses, and tumor–immune interactions.The resulting RNA-seq data provide a resource for investigating alterations in immune cell–associated gene signatures, metabolic pathways, and microenvironmental features that may underlie immune dysfunction in MASH-HCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE318726 | GEO | 2026/02/11

REPOSITORIES: GEO

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Project description:Rates of hepatocellular carcinoma (HCC) are increasing rapidly due to the epidemic of metabolic dysfunction-associated steatohepatitis (MASH). In addition to increased incidence, emerging evidence suggests that MASH driven HCC is associated with poor survival outcomes potentially due to the complex liver microenvironment which is characterized by hypoxia, steatosis, and fibrosis. Lenvatinib, is a multi-tyrosine kinase inhibitor, that is a standard of care therapy for unresected HCC, but 5-year survival rates are less than 20%. Therefore, developing treatments that inhibit cancer growth kinetics and target the tumor microenvironment to improve the therapeutic response in MASH-HCC are needed. Salsalate is a rheumatoid arthritis therapy that stimulates the AMP-activated protein kinase (AMPK) increasing fatty acid oxidation while reducing de-novo lipogenesis, fibrosis and cell proliferation pathways. Thus, we hypothesized that Salsalate could improve the therapeutic efficacy of Lenvatinib in MASH-HCC. In the current study, we show that treatment of human HCC cells with clinically relevant concentrations of Lenvatinib and Salsalate synergistically suppress proliferation and clonogenic survival, activate AMPK and inhibit the mTOR-HIF1a and Erk1/2 signaling pathways. In orthotopic xenograft and MASH-HCC mouse models Lenvatinib and Salsalate combination therapy suppressed angiogenesis and steatosis and fibrosis. RNA-sequencing revealed combination therapy enhanced mitochondria fatty acid oxidation and suppressed glycolysis, angiogenesis, fibrosis and cell cycle progression with regulatory network analysis suggesting a potential role for Activating transcription factor 3 (ATF3) and ETS-proto-oncogene-1 (ETS1). These data suggest that Lenvatinib and Salsalate combination therapy may have therapeutic potential for MASH-HCC due to effective metabolic rewiring and growth inhibition, leading to improvements in the liver microenvironment and inhibition of HCC proliferation.

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Phenylalanine Reprograms TLS Maturation and Plasma cell differentiation in MASH-HCC [Spatial Transcriptomics]

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