Mutant TP53 is an established oncogenic driver in esophageal adenocarcimona (EAC), but mechanisms regulating mutant p53 protein folding remain incompletely solved. In their study on page 996, Ray and colleagues show that a protein fragment from gene related to anergy in lymphocytes isoform 1 (GRAIL1), an E3 ubiquitin ligase, interacts with DNAJA1, a known mutant p53-stabilizing protein chaperone. Furthermore, the fragment, termed Frag-J, locks DNAJA1 in complex with protein chaperone partner Hsp70. The authors found that locking the DNAJA1-Hsp70 complex inhibits chaperone activity, promoting misfolded mutant p53 degradation and inhiting EAC cell line and patient-derived organoid growth. The cover image features an immunofluorescent image of a dysplastic Barrett’s esophagus organoid treated with a peptide derived from Frag-J – Pep-J – and stained with fluorescent antibody conjugates specific for p53 (green) and epithelial marker EpCAM (red). The study ultimately presents GRAIL1-derived Pep-J as a therapeutic modality with potential therapeutic efficacy against misfolded mutant p53-driven EAC. This study is also Highlighted on page 993.