Mutations in the Txnip PPXY motifs protect against myocardial infarction despite enhanced protein stability

This study reveals that Txnip's conserved PPXY motifs regulate its cytotoxicity independently of its canonical redox and metabolic functions. Mutating motifs (PPXY-to-AAXA) uncouples Txnip function from cell death, stabilizes the protein by preventing Itch-mediated ubiquitination, and confers striking cardioprotection in knock-in mice after myocardial infarction. Despite elevated Txnip levels, mutant hearts show reduced AP-1 signaling and improved survival, demonstrating that PPXY-dependent pathways, not Txnip abundance, drive cardiotoxicity.