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

Authors

Rabab S Hamad, Marwa S Zaghloul, Ahmed Shata, Doaa N Abdallah, Alshaimaa H Abd Elmaksoud, Sherihan I Gouda, Nesreen Elsayed Morsy, Shereen Hamed, Sameh Saber

Published in

Progress in biophysics and molecular biology. Pages 101951. Sep 18, 2026. Epub Sep 18, 2026.

Abstract

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.

PMID:
42759775
Bibliographic data and abstract were imported from PubMed on 19 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.