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While Nrf2 is globally suppressed in COPD via promoter hypermethylation (138), its sustained but inadequate activation in macrophages drives ferritinophagy via NCOA4 (139)

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Given that the rs13107325 (p.Ala391Thr) variant has been linked to 22 clinical phenotypes 44,313 , an important question is whether this pleiotropy reflects the diverse roles of Mn as an enzymatic cofactor or a common downstream signaling mechanism