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.
Authors
- Toru Hiratsuka (ORCID: https://orcid.org/0000-0002-5359-2690)
- Yataro Daigo (ORCID: https://orcid.org/0000-0002-0915-3025)
- Akihiro Nita (ORCID: https://orcid.org/0000-0003-2647-5445)
- Motoyuki Ogawa (ORCID: https://orcid.org/0000-0002-2322-5021)
- Hidenori Ichijo
- Toshiro Moroishi (ORCID: https://orcid.org/0000-0001-6419-3882)
- Akinori Kanai (ORCID: https://orcid.org/0000-0003-1555-6768)
- Isao Naguro (ORCID: https://orcid.org/0000-0002-0338-8026)
- Atsushi Takano (ORCID: https://orcid.org/0000-0002-8664-4821)
- Masafumi Kuroda
- Yohei Miyagi
- Ziwei Wang
- Shinya Sato
- Takao Fujisawa
- Yutaka Suzuki
- Mina Yano
- Satoshi Takenaka
- Daisuke Taniguchi
Institutions
- Chiba University (JP)
- Shiga University of Medical Science (JP)
- Kanagawa Prefectural Hospital Organization (JP)
- Osaka City University (JP)
- Juntendo University (JP)
- Shiga University of Medical Science Hospital (JP)
- Osaka International Cancer Institute (JP)
- University of Tokyo Hospital (JP)
- Japan Research Institute (JP)
- Kanagawa Cancer Center
- The University of Tokyo (JP)
- Kumamoto University (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-05-30
- DOI
- https://doi.org/10.1016/j.celrep.2026.117410
- Primary Topic
- Fibroblast Growth Factor Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Takeda Science Foundation
- Nakatomi Foundation
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- Research Organization of Information and Systems
- Kato Memorial Bioscience Foundation
- Yasuda Memorial Medical Foundation
- MSD Life Science Foundation, Public Interest Incorporated Foundation
- Japan Society for the Promotion of Science
- Institute of Medical Science, University of Tokyo
- Moonshot Research and Development Program