Chemotherapy-Induced Oral Mucosal Injury Is Defined by p53 Activation, Cell Cycle Arrest and Diverse Epithelial Progenitor Dynamics

Summary Chemotherapy-induced oral mucositis is a common and debilitating complication, yet the mechanisms underlying oral mucosa injury and repair remain poorly defined. Using a mouse model of 5-fluorouracil (5-FU)–induced mucositis, we define gene networks and oral mucosal cellular landscape dynamics in response to chemotoxic stress. We show that 5-FU–induced epithelial atrophy is driven primarily by cell cycle arrest rather than apoptosis, despite concurrent activation of p53-dependent transcriptional programs linked to both cell fates within individual cells. Relative to intestine, the recovering oral mucosa exhibits a more effective cell cycle checkpoint response and uniquely undergoes metabolic reprogramming toward lipid oxidation. Single-cell RNA sequencing revealed putative epithelial progenitor populations with distinct responses to chemotherapy, including chemoresistant cells with a p53– and AP-1 complex gene signature, reminiscent of lung transitional cell states. These findings define diverse progenitor dynamics and p53-driven responses as key determinants of oral mucosal injury and repair following chemotherapy. Competing Interest Statement The authors have declared no competing interest.