Biophysical and molecular determinants of NCOA4-mediated ferritinophagy at the ferroptosis-inflammation interface: Compartmental iron transport, lipid oxidation, and causal constraints.

Ferritinophagy links molecular recognition of ferritin to the redistribution of redox-active iron across intracellular compartments. This critical narrative review examines nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy as a multiscale process in which NCOA4-FTH1 binding and ferritin condensation govern cargo organization, TAX1BP1-dependent trafficking controls lysosomal delivery, ferric reduction and ferrous export determine iron speciation and transport, and membrane composition and antioxidant kinetics set the threshold for ferroptotic lipid peroxidation. This biophysical-molecular perspective asks which spatially and temporally resolved steps have been demonstrated within the same experimental system. The strongest evidence supports NCOA4-dependent ferritin trafficking and degradation as a regulated source of bioavailable iron and a context-dependent determinant of ferroptotic competence. Evidence for a conserved downstream NCOA4-to-NLRP3 pathway is substantially weaker and remains model-dependent. Ferritinophagy-associated injury can instead yield cell-autonomous inflammasome activation, non-inflammasome signaling such as cGAS-STING activation, or intercellular transfer between parenchymal, immune, and stromal cells. We distinguish sequential cell-autonomous, parallel-convergence, and tissue-level/intercellular models rather than assuming a single linear axis. A study-level evidence map and causal-validation framework specify the measurements needed to connect these scales: ferritinophagy flux, compartment-resolved iron, lipid-peroxidation kinetics, selective ferroptosis rescue, lysosomal integrity, complete inflammasome outputs, temporal ordering, restoration, and cell-type localization. The central unresolved problem is when ferritin-derived iron becomes an execution-relevant, membrane-proximal pool and whether inflammatory signaling is coupled in the same cell or through intercellular transfer.