Unveiling the role of soil in urban vegetation greenness: City-scale evidence from field sampling across green spaces in Shanghai

Hanxin Tang

doi:10.1016/j.jclepro.2026.149150

Homocysteine promotes ferroptosis through NCOA4-mediated ferritinophagy in THP-1 macrophages

2026-08-12

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OA

AI

Y

YY Yu Yang

W

WZ Weiya Zhang

D

DH Dandan Huang *

DOI：10.3389/fphys.2026.1905092

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IntroductionAs an independent risk factor for atherosclerosis (AS); hyperhomocysteinemia (HHcy) exerts its pathogenic effects primarily through the induction of macrophage ferroptosis. As a selective autophagic process mediated by nuclear receptor coactivator 4 (NCOA4); ferritinophagy directly influences ferroptosis via its regulation of cellular iron balance. However; whether homocysteine (Hcy) regulates macrophage ferroptosis through ferritinophagy remains unclear.MethodsHuman acute monocytic leukemia (THP-1) cells were differentiated into macrophages and subsequently treated with Hcy. Ferroptosis was assessed by measuring glutathione (GSH) levels; reactive oxygen species (ROS); Fe²⁺ content; and mitochondrial morphology. Protein expression of NCOA4; FTH1; and GPX4 was examined; and GPX4 methylation was evaluated. The involvement of ferritinophagy was further verified using the ferroptosis inhibitor ferrostatin‑1 (Fer‑1) and the inducer Erastin. Activation of the IL‑6/STAT3 signaling pathway was also examined; along with its reciprocal regulation with ferroptosis.ResultsHcy treatment promoted ferroptosis in THP‑1 macrophages; as indicated by decreased GSH levels; increased ROS and Fe²⁺ levels; and characteristic mitochondrial morphological changes. Hcy also enhanced GPX4 methylation; resulting in reduced GPX4 expression. Mechanistically; Hcy upregulated NCOA4 and downregulated FTH1; suggesting activation of NCOA4‑mediated ferritinophagy; these effects were reversed by Fer‑1 and augmented by Erastin. In addition; Hcy activated the IL‑6/STAT3 pathway; and its crosstalk with ferroptosis was confirmed by the reciprocal modulation with Fer‑1 and Erastin.DiscussionCollectively; our study indicates that Hcy promotes ferroptosis in THP-1 macrophages through NCOA4-mediated ferritinophagy; and the IL-6/STAT3 signaling pathway plays a key role in this process. Therefore; targeting Hcy may represent a potential treatment strategy for AS.

Keywords:

ferroptosis

ferritinophagy

THP-1 cells

atherosclerosis

homocysteine

Homocysteine promotes ferroptosis through NCOA4-mediated ferritinophagy in THP-1 macrophages

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