FTH1 mRNA-Protein Discordance in Cardiac Ferroptosis: Multilayer Posttranscriptional and Degradative Control.

Ferritin heavy Chain 1 (FTH1) is a key protective factor against ferroptosis in the heart, yet its protein abundance can diverge from transcript levels in cardiac ferroptosis contexts. Since resistance to ferroptosis depends on FTH1 protein abundance rather than transcript levels and its ferroxidase activity cannot be readily compensated by other ferritin subunits, this mismatch is functionally consequential. This review organizes the evidence into three regulatory layers acting downstream of transcription. Iron regulatory protein/iron-responsive element (IRP/IRE) signaling gates ribosome recruitment at the 5 '-untranslated region before translation begins. Epitranscriptomic marks and RNA-binding proteins (RBPs) then route the transcript toward decay or translation, with the N6-methyladenosine (m6A) reader YTHDF2 acting in opposite directions across cardiac contexts. Finally, nuclear receptor Coactivator 4 (NCOA4) delivers assembled ferritin for lysosomal degradation, depleting FTH1 protein independently of transcript level. Together, these mechanisms provide an integrated framework for understanding the mRNA-protein discordance of FTH1 and its contribution to cardiac ferroptosis susceptibility. We also discuss how this framework may inform layer-specific therapeutic strategies and identify the measurements that are missing (labile iron pool, ferritin iron loading, and ferritinophagic flux) before mechanistic insight can translate into clinical cardioprotection.