Iron homeostasis depends on the coordinated regulation of iron uptake, storage, utilization and export to maintain cellular metabolism and redox balance. Ferritinophagy is an iron‑specific form of autophagy mediated by the selective cargo receptor nuclear receptor coactivator 4. By delivering ferritin to the autophagy‑lysosome system for degradation and releasing Fe²+, ferritinophagy regulates the intracellular labile iron pool and influences reactive oxygen species generation, lipid peroxidation and the ferroptosis threshold. Fibrosis is an aberrant repair response driven by chronic injury and is characterized by persistent inflammation, fibroblast activation and excessive extracellular matrix deposition. Increasing evidence has indicated that iron deposition and iron metabolic reprogramming are common features across a number of fibrotic disorders. Oxidative stress resulting from disrupted iron homeostasis can interact with the TGF‑β signaling network to promote tissue remodeling. As an upstream regulatory mechanism, ferritinophagy may connect abnormal iron metabolism, oxidative stress, ferroptosis and profibrotic signaling through modulation of bioavailable iron, with bidirectional effects depending on cell type and disease stage. The present review summarizes the molecular basis and regulatory networks of ferritinophagy, whilst integrating recent advances regarding its role in fibrosis across different tissues or organs. It further discusses the potential balancing role of ferritinophagy in parenchymal cell injury and effector cell fate regulation, highlighting antifibrotic strategies targeting upstream metabolic regulation based on modulation of the ferroptosis threshold.
