FGF21 suppresses hepatocellular carcinoma by driving competitive cell-cell interactions.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. However, the molecular events underlying its early development are poorly understood. Here, using a murine liver cell competition model combined with single-cell and spatial transcriptomic profiling, we show that fibroblast growth factor 21 (FGF21) mediates tumor-suppressive cell competition in the liver. We demonstrated that FGF21, secreted by oncogenic hepatocytes, drives the directional migration of adjacent normal hepatocytes, leading to the mechanical elimination of oncogenic cells. Mechanistically, we identified NOS3-mediated S-nitrosylation of ASK1 at an evolutionarily conserved cysteine residue (C869) as a critical post-translational modification that induces FGF21 expression and triggers cell competition. Modulation of FGF21 levels in distinct oncogenic contexts influences HCC progression. FGF21 depletion accelerates tumor development, whereas its overexpression suppresses tumor formation. These findings highlight FGF21 as a physiological driver of tumor-suppressive cell competition and underscore its potential relevance as a promising therapeutic target in early-stage HCC.