Letter to "NR1D2 Knockdown Alleviates Myocardial Infarction Through Nrf2 Signaling Pathway Activation".

Targeting iron-dependent ferroptosis represents a promising strategy to limit myocardial infarction (MI) injury. Wang et al. recently demonstrated that silencing the circadian receptor NR1D2 (REV-ERBβ) preserves ischemic myocardium by activating the Nrf2/GPX4 antioxidant axis. While their mechanistic rigor is commendable, translating NR1D2 modulation to the clinic reveals a pharmacological paradox. Prior studies show that NR1D2 agonists also prevent post-MI heart failure via metabolic remodeling, contrasting with the benefits of NR1D2 inhibition reported here. We argue this discrepancy hinges on temporal specificity: acute knockdown likely halts immediate ferroptotic damage and subsequent DAMP-driven sterile inflammation, whereas subacute agonism supports metabolic recovery. Moving beyond the bench, systemic Nrf2 hyperactivation poses oncogenic risks, and compensatory NR1D1 upregulation may undermine long-term efficacy. Consequently, realizing the therapeutic potential of the NR1D2/Nrf2 axis requires mapping its dynamic post-MI expression to define exact intervention windows, alongside engineering cardiac-homing nanocarriers to bypass systemic toxicity and ensure precise myocardial salvage.