| First Author | Shi X | Year | 2024 |
| Journal | Sci Adv | Volume | 10 |
| Issue | 43 | Pages | eado9311 |
| PubMed ID | 39441934 | Mgi Jnum | J:357580 |
| Mgi Id | MGI:7763298 | Doi | 10.1126/sciadv.ado9311 |
| Citation | Shi X, et al. (2024) Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice. Sci Adv 10(43):eado9311 |
| abstractText | 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-AP signaling. Compromised MoMFs could present as tumor-associated macrophage phenotype rendering tumor immune microenvironment for MASH-HCC transition. |
