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COMM domain containing 4 inhibits hephaestin and ferroportin to enhance neuronal ferroptosis by disturbing the Cu-Fe balance in amyotrophic lateral sclerosis

Xingli Tan,Xiaoli Su,Ying Wang,Weiwei Liang,Di Wang,Di Huo,Hongyong Wang,Yan Qi,Wenmo Zhang,Ling Han,Dongmei Zhang,Ming Wang,Jing Xu,Shuyu Wang,Jing Wang,Honglin Feng

Dysregulation of copper and iron homeostasis contributes to the progression of amyotrophic lateral sclerosis (ALS), but the role and mechanism of COMM domain containing 4 (COMMD4) in ALS remains unclear. In this research, we showed that the expression of COMMD4 was upregulated in ALS cells and animal models. The increased COMMD4 induced neuronal ferroptosis by disrupting the Cu-Fe balance. Mechanistic studies indicated that COMMD4 inhibited ferroportin (FPN)-mediated neuronal iron efflux by inhibiting intracellular copper and hephaestin (HEPH). Our findings demonstrated that COMMD4 depletion exerts neuroprotective effects on ALS by increasing intracellular copper and activating HEPH/FPN pathway, rather than affecting the interaction between HEPH and FPN. Targeting COMMD4 and its downstream signaling pathways may offer potential therapeutic avenues for ALS.