FGF21 Suppresses Hepatocellular Carcinoma by Driving Competitive Cell–Cell Interactions

ABSTRACT: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, yet the molecular events underlying its early development are poorly understood. Here, we identify fibroblast growth factor 21 (FGF21), secreted from oncogenic hepatocytes, as a key inducer of cell competition that suppresses tumor initiation. Using a newly developed mouse model in combination with single-cell and spatial transcriptomics, we demonstrate that FGF21 activates surrounding normal hepatocytes to promote mechanical cell competition. Mechanistically, we show that S-nitrosylation of ASK1 at cysteine 869 is a critical post-translational modification that drives FGF21 expression and triggers cell competition. Modulating FGF21 expression levels in various oncogenic hepatocytes impacted HCC development—its depletion accelerated, whereas its overexpression markedly suppressed, tumor formation. These findings establish FGF21 as a physiological driver of tumor-suppressive cell competition and underscore its therapeutic potential in early-stage HCC.

INSTRUMENT(S):

ORGANISM(S): Canis Familiaris (dog) (canis Lupus Familiaris)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Motoyuki Ogawa  

LAB HEAD: Hidenori Ichijo

PROVIDER: PXD065286 | Pride | 2026-10-05

REPOSITORIES: Pride