Ferritinophagy and organ injury

Ferritinophagy is a selective form of macroautophagy/autophagy that mediates the degradation of ferritin complexes, releasing stored iron, and maintaining intracellular iron homeostasis. Proper regulation of ferritinophagy is essential for cellular adaptation to metabolic stress, whereas dysregulation disrupts iron balance and contributes to pathological processes. Excessive ferritinophagy leads to iron overload and reactive oxygen species accumulation, driving oxidative stress, ferroptosis, and inflammation, which are key contributors to cellular injury and progressive organ dysfunction. Despite advances in our understanding of autophagy and ferroptosis, the specific role of ferritinophagy in organ-specific injury remains unclear. In this review, we provide a comprehensive overview of the molecular mechanisms of ferritinophagy and critically examine its emerging roles in the pathogenesis of injuries to the heart, liver, lungs, and kidneys. We further highlight the therapeutic potential of targeting ferritinophagy and propose future research directions aimed at harnessing this pathway for the treatment of organ injuries.Abbreviations: 3-MA: 3-methyladenine; ACO1/IRP1: aconitase 1; AKI: acute kidney injury; ARDS: acute respiratory distress syndrome; ATG: autophagy related; BECN1: beclin 1; CARM1/PRMT4: coactivator associated arginine methyltransferase 1; CIRBP: cold inducible RNA binding protein; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; ELAVL1: ELAV like RNA binding protein 1; Fer-1: ferrostatin-1; FTH1: ferritin heavy chain 1; GABARAP: GABA type A receptor-associated protein; GPX4: glutathione peroxidase 4; HAMP/hepcidin: hepcidin antimicrobial peptide; HCC: hepatocellular carcinoma; HERC2: HECT and RLD domain containing E3 ubiquitin protein ligase 2; HSCs: hepatic stellate cells; IL13: interleukin 13; IL6: interleukin 6; I/R: ischemia-reperfusion; IRE: iron-responsive element; IREB2/IRP2: iron responsive element binding protein 2; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MDA: malondialdehyde; MIOX: myo-inositol oxygenase; NCOA4: nuclear receptor coactivator 4; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; ROS: reactive oxygen species; SIRT1: sirtuin 1; SLC40A1/ferroportin: solute carrier family 40 member 1; STAT3: signal transducer and activator of transcription 3; STEAP3: STEAP3 metalloreductase; TFRC/TfR1: transferrin receptor; USP11: ubiquitin specific peptidase 11; YAP1: Yes1 associated transcriptional regulator.