Cell competition is a social cellular phenomenon in which unfit cells are 
selectively eliminated to maintain tissue homeostasis.1-3 Recent studies have 
revealed that mechanical forces induce competitive cell-cell interactions in 
Drosophila.4-6 This mechanical cell competition has also been reported to play 
an important role in mammalian cells, using Madin-Darby canine kidney (MDCK) 
cells depleted of a polarity regulator Scribble in a tetracycline-inducible 
manner (scribKD cells).7scribKD cells are hypersensitive to crowding due to the 
lower homeostatic density than wild-type (WT) cells,7,8 and in the context of 
cell competition, scribKD cells are compacted and eliminated by WT cells.7-10 
Although p38 and p53 are involved in this process,7,10 the molecular mechanism 
by which WT cells recognize and mechanically eliminate scribKD cells remains 
unclear. Here, we report that scribKD cells secrete fibroblast growth factor 21 
(FGF21) to drive cell competition. Knockdown of FGF21 in scribKD cells or loss 
of FGFR1 in WT cells suppresses cell competition, suggesting that WT cells 
recognize scribKD cells through FGF21. FGF21-containing culture medium of 
scribKD cells activates cell motility. Moreover, FGF21 promotes the compression 
and elimination of scribKD cells by attracting surrounding WT cells. We also 
demonstrate that activation of the apoptosis signal-regulating kinase 1 
(ASK1)-p38 pathway in scribKD cells induces FGF21 to drive cell competition. Our 
findings reveal a mechanism whereby WT cells mechanically eliminate scribKD 
cells and propose a new function for FGF21 in cell-cell communication.