Targeting Ncoa4-mediated ferritinophagy ameliorates arsenism by restoring redox homeostasis and suppressing ferroptosis

Arsenic induces time-dependent ferroptosis in zebrafish embryonic (ZF4) cells. • Ncoa4-mediated ferritinophagy plays a critical role in arsenic-induced ferroptosis. • Early arsenic exposure suppresses Ncoa4 and accumulates FTH1, delaying ferroptosis. • Late-phase arsenic activates Ncoa4, promoting ferritin degradation and iron release. • Melatonin alleviates arsenic-induced ferroptosis via Nrf2-dependent antioxidant pathway. Arsenic (As) is a widely distributed toxic pollutant worldwide, posing severe threats to the health of animals and plants. Transcriptomic analysis of zebrafish embryonic cells (ZF4) revealed that exposure to trivalent arsenic (arsenite, As 3+ ) significantly altered levels of FTH1 (ferritin heavy chain 1) and Ncoa4 (nuclear receptor coactivator 4), and was closely associated with the proteasome pathway. Based on these findings, we further investigated the mechanisms underlying As-induced cell death and potential intervention strategies. The results showed that As induced autophagic cell death. Ferroptosis occurred as a late event and was regulated by Ncoa4-mediated ferritinophagy: during the early stage of As exposure, FTH1 accumulated independently of Ncoa4 changes, likely as a protective iron-sequestering response; whereas in the late stage, Ncoa4 activation promoted ferritin degradation and iron release, ultimately triggering ferroptosis. Moreover, melatonin (1 mmol/L) significantly alleviated As-induced ferroptosis by strengthening cellular antioxidant capacity through activation of the Nrf2 signaling pathway. Overall, this study reveals a critical regulatory role of Ncoa4 in As-induced ferroptosis and provides experimental evidence supporting targeted intervention strategies for arsenic poisoning. Download: Download high-res image (284KB) Download: Download full-size image