Fungus Rhizopus arrhizus promotes MASLD-associated hepatocellular carcinoma through generating kynurenic acid

Fungi are crucial components of the human gut microbiota. Here, we investigated the role of fungi in metabolic dysfunction-associated steatotic liver disease-associated hepatocellular carcinoma (MASLD-HCC). Rhizopus arrhizus was the top enriched fungus across the progression from MASLD to MASLD-HCC, accelerating tumorigenesis in multiple mouse models. R. arrhizus-conditioned medium increased cell proliferation while reducing cell cycle arrest and apoptosis in human MASLD-HCC cells. Kynurenic acid (KYNA) was identified as the crucial metabolite generated from R. arrhizus, and its upregulation was confirmed in portal vein, liver tissues, and stools of R. arrhizus-treated mice. KYNA promoted the proliferation of MASLD-HCC cells and accelerated tumorigenesis in mice. Mechanistically, KYNA directly bound to IQ motif containing GTPase activating protein 1 (IQGAP1) in tumor cells and activated the oncogenic mitogen-activated protein kinase (MAPK) signaling pathway, thereby facilitating MASLD-HCC development. In summary, R. arrhizus is a pathogenic fungus that promotes MASLD-HCC by producing KYNA. Blocking this host-fungi interaction is a potential therapeutic strategy to suppress MASLD-HCC.