Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice

Menée à l'aide de lignées cellulaires, de modèles murins ainsi que d'échantillons tissulaires hépatiques et d'échantillons sériques issus de patients présentant une stéatohépatite associée à un dysfonctionnement métabolique (MASH) et atteints ou non d'un carcinome hépatocellulaire, cette étude met en évidence un mécanisme par lequel une population de macrophages dérivés de monocytes contribuent à la progression d'une MASH vers un carcinome hépatocellulaire en rendant le microenvironnement tumoral favorable à cette transformation

Résumé en anglais

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. FGF21 could prevent MASH-HCC transition via preservation of KC pool homeostasis and inhibition of S1P-S1PR2-YAP signaling.