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YOD1 promotes ferroptosis in acute lung injury by deubiquitination of NCOA4

Year: 2025

Type: article

Abstract: Acute lung injury (ALI) is a prevalent critical condition for which effective treatments remain elusive. Ferroptosis plays a significant role in the pathophysiology of ALI. The deubiquitinating enzyme YOD1 is implicated in the regulation of infectious diseases; however, its specific role in ALI and ferroptosis is not yet fully understood. In this study, we observed that YOD1 expression was notably elevated in the lung tissue and primary alveolar type II (ATII) cells of mice subjected to lipopolysaccharide (LPS)-induced ALI. Moreover, YOD1 deficiency significantly mitigated ferroptosis and damage to the alveolar epithelial barrier. Mechanistically, YOD1 interacts directly with NCOA4 through its OTU domain, inhibiting K48-linked ubiquitination at the K343/K353 lysis residue of NCOA4, thus facilitating NCOA4-mediated autophagic degradation of FTH1 and promoting ferroptosis. Overall, our findings indicate that YOD1 regulates NCOA4 via deubiquitination, suggesting it may serve as a potential therapeutic target for ALI. This study reveals that the deubiquitinase YOD1 is upregulated in LPS-induced acute lung injury (ALI) and exacerbates ferroptosis by deubiquitinating and stabilizing NCOA4, thereby promoting NCOA4-mediated ferritinophagy. YOD1 deficiency alleviated lung injury, suggesting YOD1 as a potential therapeutic target for ALI.

Source: Communications Biology

DOI: 10.1038/s42003-025-09237-8