Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China.
Sci Adv. 2024 Oct 25;10(43):eado9311. doi: 10.1126/sciadv.ado9311. Epub 2024 Oct 23.
Metabolic dysfunction-associated steatohepatitis is well accepted as a potential precursor of hepatocellular carcinoma. Previously, we reported that fibroblast growth factor 21 (FGF21) revealed a novel anti-inflammatory activity via inhibiting the TLR4-IL-17A signaling, which could be a potential anticarcinogenetic mechanism to prevent to MASH-HCC transition. Here, we set out to determine whether FGF21 has a major impact on Kupffer cells' (KCs) ability during MASH-HCC transition. We found aberrant hepatic FGF21 and KC pool in human MASH-HCC. Lack of FGF21 up-regulated ALOX15, which converted the oxidized fatty acids to induce excessive KC death and mobilization of monocyte-derived macrophages (MoMFs) for KC replacement. Lack of FGF21 oversupplied free fatty acids for sphingosine-1-phosphate (S1P) cascade synthesis to mediate MASH-HCC transition via S1P-YAP signaling and cross-talk between tumor cells and macrophages. In conclusion, lack of FGF21 accelerated MASH-HCC transition via the S1P-YAP signaling. Compromised MoMFs could present as tumor-associated macrophage phenotype rendering tumor immune microenvironment for MASH-HCC transition.
代谢相关脂肪性肝炎被认为是肝细胞癌的潜在前体。此前，我们报道称，成纤维细胞生长因子 21（FGF21）通过抑制 TLR4-IL-17A 信号通路发挥新的抗炎活性，这可能是一种潜在的抗癌发生机制，可防止 MASH-HCC 转变。在这里，我们着手确定 FGF21 是否对 MASH-HCC 转变过程中库普弗细胞（KCs）的功能有重大影响。我们发现人类 MASH-HCC 中存在异常的肝 FGF21 和 KC 池。FGF21 的缺乏会上调 ALOX15，将氧化脂肪酸转化为诱导过度 KC 死亡和单核细胞衍生的巨噬细胞（MoMFs）向 KC 替代的迁移。FGF21 的缺乏会过度供应游离脂肪酸用于合成鞘氨醇-1-磷酸（S1P）级联反应，通过 S1P-YAP 信号转导和肿瘤细胞与巨噬细胞之间的串扰来介导 MASH-HCC 转变。总之，FGF21 的缺乏通过 S1P-YAP 信号转导加速了 MASH-HCC 的转变。受损的 MoMFs 可能表现为肿瘤相关巨噬细胞表型，为 MASH-HCC 的转变提供肿瘤免疫微环境。
