Ferritinophagy in inflammatory and autoimmune diseases: Mechanistic insights and therapeutic potentials

Ferritinophagy, a selective form of autophagy mediated by nuclear receptor coactivator 4 (NCOA4), degrades ferritin to regulate intracellular iron homeostasis and has emerged as an important process in inflammatory and autoimmune diseases. By controlling ferritin turnover, ferritinophagy affects labile iron levels and ferroptosis, an iron-dependent cell death driven by lipid peroxidation, and interacts with multiple immune regulatory pathways. This process is modulated by signaling networks such as MAPK, cGAS-STING, NF-κB, AMPK/mTOR, and NRF2, which link iron metabolism to inflammatory responses. Aberrant ferritinophagy has been implicated in conditions including sepsis, osteoarthritis, asthma, rheumatoid arthritis, and systemic lupus erythematosus. Preclinical studies demonstrate that strategies such as inhibiting the JNK-JUN or cGAS-STING pathways, or applying iron chelators like deferoxamine, can reduce iron overload, limit ferroptosis, and attenuate inflammation. Despite these advances, further work is needed to delineate disease-specific regulatory mechanisms and to translate ferritinophagy modulation into safe and effective therapies. This review summarizes current mechanistic insights and therapeutic prospects, highlighting ferritinophagy as a promising target for managing inflammatory and autoimmune disorders.