FSP1 as the convergent hub of autophagy and ubiquitination governing ferroptosis in monocrotaline‐induced pulmonary arterial hypertension
- 1Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases Fudan University Shanghai China
- 2National Clinical Research Center for Interventional Medicine Shanghai China
Abstract
Introduction: The interaction mechanism between autophagy and ferroptosis in pulmonary arterial hypertension (PAH) remains unclear. We identified FSP1 as a core molecular node linking these two critical processes. Mechanistically, the degradation of FSP1 is coordinately regulated by NBR1‐mediated autophagic flux and RNFT1‐driven K63‐linked ubiquitination, collectively exacerbating ferroptosis and PAH progression. Combination therapy involving FSP1 overexpression and the autophagy inhibitor Apelin‐13 synergistically alleviates PAH in rats by stabilizing FSP1 and suppressing ferroptosis. This study not only reveals a dual‐pathway mechanism regulating FSP1 stability and validates a novel therapeutic strategy targeting FSP1 degradation but also provides a novel combined intervention strategy for the clinical treatment of PAH.
Background and objective: The interaction between autophagy and ferroptosis in pulmonary arterial hypertension (PAH) remains poorly understood. This study aims to elucidate the role of ferroptosis suppressor protein 1 (FSP1) as a central molecular node linking these processes and to explore a combined therapeutic strategy targeting FSP1 degradation for PAH intervention.
Methods: Molecular biology techniques were employed to analyse FSP1 degradation pathways, focusing on NBR1‐mediated autophagic flux and RNFT1‐driven K63‐linked ubiquitination. A rat PAH model was established to evaluate the therapeutic efficacy of combining FSP1 overexpression with the autophagy inhibitor Apelin‐13.
Results: FSP1 stability was coordinately regulated by autophagy and ubiquitination: NBR1 promoted autophagic degradation of FSP1, while RNFT1 exacerbated this process via K63‐linked ubiquitination, collectively accelerating ferroptosis and PAH progression. The combination of FSP1 overexpression and Apelin‐13 synergistically stabilized FSP1, suppressed ferroptosis, and alleviated PAH symptoms in rats.
Conclusion: This study reveals a dual‐pathway mechanism governing FSP1 stability through autophagy‐ubiquitination crosstalk, highlighting its critical role in ferroptosis‐driven PAH. The combination therapy targeting FSP1 degradation presents a novel strategic approach for clinical PAH treatment.
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BibTeX
@article{chen2026fsp1,
title = {{FSP1 as the convergent hub of autophagy and ubiquitination governing ferroptosis in monocrotaline‐induced pulmonary arterial hypertension}},
author = {Dandan Chen and Qi Jin and Lei Zhang and Wenzhi Pan and Daxin Zhou and Junbo Ge and Lihua Guan},
journal = {Clinical and Translational Medicine},
year = {2026},
month = nov,
doi = {10.1002/ctm2.70822},
url = {https://doi.org/10.1002/ctm2.70822},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - FSP1 as the convergent hub of autophagy and ubiquitination governing ferroptosis in monocrotaline‐induced pulmonary arterial hypertension
AU - Dandan Chen
AU - Qi Jin
AU - Lei Zhang
AU - Wenzhi Pan
AU - Daxin Zhou
AU - Junbo Ge
AU - Lihua Guan
PY - 2026
DA - 2026/11/05
JO - Clinical and Translational Medicine
DO - 10.1002/ctm2.70822
UR - https://doi.org/10.1002/ctm2.70822
AB - Introduction: The interaction mechanism between autophagy and ferroptosis in pulmonary arterial hypertension (PAH) remains unclear. We identified FSP1 as a core molecular node linking these two critical processes. Mechanistically, the degradation of FSP1 is coordinately regulated by NBR1‐mediated autophagic flux and RNFT1‐driven K63‐linked ubiquitination, collectively exacerbating ferroptosis and PAH progression. Combination therapy involving FSP1 overexpression and the autophagy inhibitor Apelin‐13 synergistically alleviates PAH in rats by stabilizing FSP1 and suppressing ferroptosis. This study not only reveals a dual‐pathway mechanism regulating FSP1 stability and validates a novel therapeutic strategy targeting FSP1 degradation but also provides a novel combined intervention strategy for the clinical treatment of PAH. Background and objective: The interaction between autophagy and ferroptosis in pulmonary arterial hypertension (PAH) remains poorly understood. This study aims to elucidate the role of ferroptosis suppressor protein 1 (FSP1) as a central molecular node linking these processes and to explore a combined therapeutic strategy targeting FSP1 degradation for PAH intervention. Methods: Molecular biology techniques were employed to analyse FSP1 degradation pathways, focusing on NBR1‐mediated autophagic flux and RNFT1‐driven K63‐linked ubiquitination. A rat PAH model was established to evaluate the therapeutic efficacy of combining FSP1 overexpression with the autophagy inhibitor Apelin‐13. Results: FSP1 stability was coordinately regulated by autophagy and ubiquitination: NBR1 promoted autophagic degradation of FSP1, while RNFT1 exacerbated this process via K63‐linked ubiquitination, collectively accelerating ferroptosis and PAH progression. The combination of FSP1 overexpression and Apelin‐13 synergistically stabilized FSP1, suppressed ferroptosis, and alleviated PAH symptoms in rats. Conclusion: This study reveals a dual‐pathway mechanism governing FSP1 stability through autophagy‐ubiquitination crosstalk, highlighting its critical role in ferroptosis‐driven PAH. The combination therapy targeting FSP1 degradation presents a novel strategic approach for clinical PAH treatment.
SN - 2001-1326
ER -