Proteostatic defect drives biophysical remodeling that triggers cell competition.

Cell competition is a fundamental tissue-surveillance process in which less-fit "loser" cells are actively eliminated by "winner" neighbors. Here, we establish a mammalian epithelial model of ribosomal protein insufficiency using Madin-Darby canine kidney (MDCK) cells with tetracycline-inducible shRNA targeting ribosomal protein large subunit 24 (Rpl24). When Rpl24-knockdown cells are co-cultured with normal cells, Rpl24-knockdown cells undergo apoptosis through cell competition with surrounding normal cells. Rpl24 knockdown disrupts protein homeostasis, leading to cytoplasmixc protein aggregates. The chemical chaperone 4-phenylbutyric acid (4-PBA) diminishes aggregate accumulation and markedly reduces competitive cell death. Proteostasis disruption also remodels cellular biophysics; Rpl24-knockdown cells exhibit lower homeostatic density, increased cell area, and reduced cell-surface tension. Importantly, these biophysical alterations are reversed by 4-PBA. Together, our findings reveal that ribosomal protein insufficiency links proteostatic stress to biophysical "loser" traits, establishing proteostasis-dependent biophysical remodeling as a key determinant of competitive cell elimination.