Background and Purpose Ferroptosis is a new form of cell death
discovered in recent years. PH is a pulmonary circulatory disease
partially characterized by small pulmonary vessel remodeling and
fibrosis. However, researchers have not clearly determined whether
ferroptosis is involved in PH. Here, this study examined the role and
regulatory mechanism of ferroptosis in PH and pulmonary fibrosis.
Experimental Approach To evaluate the occurrence of ferroptosis in rat
PH models and in hypoxic PASMCs, MDA, GSH and iron assay were performed.
The therapeutic potential of ferroptosis inhibitor fer-1 was evaluated
using echocardiography, hemodynamic analysis and ventricular weight
measurement in rat PH models. Ferroptosis-related molecule was
determined by western blotting and RT-PCR. Changes in autophagy and
fibrosis were analyzed by western blotting analysis, RT-PCR and
immunofluorescence. Key Results Ferroptosis was existence in vivo and
vitro PH models. The fer-1 significantly improved the pathological
symptoms of PH and inhibited the occurrence of pulmonary vascular
fibrosis. GPX4 was significantly lower expression in PH models, and
serves as a key driver of PH-related ferroptosis. A KEGG pathway
analysis and RT-PCR detection revealed that GPX4 drives ferroptosis in
an autophagy-dependent manner. The RIP experiment verified that WTAP
bound to the GPX4 pre-mRNA, induced m6A methylation and promoted its
pre-mRNA degradation, thereby reducing the expression of GPX4 in hypoxic
PASMCs. Conclusion and Implications This study proposed ferroptosis as a
novel form of cell death in PH, and revealed the regulatory mechanism of
the ferroptosis in PH, which is based on GPX4 m6A methylation regulated
by WTAP.
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