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Endothelial USP2a-METTL16 loop potentiates IL-6 signaling via m6A-mediated IL-6R stabilization in pulmonary vascular remodeling

Cell Death & Differentiation (2026) Cite this article

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Abstract

Dysfunction of vascular endothelial cells is recognized as a critical driver in pulmonary vascular remodeling of pulmonary hypertension (PH). Although interleukin-6 (IL-6) has been firmly established as an indispensable factor leading to pulmonary vascular remodeling, its downstream molecular mechanisms remain incompletely elucidated. Here, we discover that ubiquitin-specific protease 2a (USP2a) is upregulated in lung tissues of PH patients and preclinical PH models, and in IL-6-stimulated endothelial cells. Both the endothelial cell-specific Usp2a genetic deletion and the pharmacological inhibition of USP2a with the inhibitor ML364 alleviate experimental PH manifestations. Mechanistically, USP2a attenuates the degradation of methyltransferase-like 16 (METTL16) by deubiquitination. Notably, METTL16 reciprocally enhances USP2a expression via interactions with eIF3a and eIF3b in a methyltransferase activity-independent manner, establishing a self-reinforcing USP2a-METTL16 regulatory loop. Subsequent investigations reveal that METTL16 enhances N6-methyladenosine (m6A)-mediated IL-6 receptor (IL-6R) mRNA stabilization, thereby promoting the expression of IL-6R. This study demonstrates that endothelial USP2a-METTL16 loop potentiates IL-6 signaling via IL-6R and represents a promising therapeutic target for PH.

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Fig. 1: Expression of USP2a is upregulated in PH and IL-6-stimulated endothelial cells.
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Fig. 2: USP2a induces the pro-migratory and pro-angiogenic phenotype in endothelial cells.
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Fig. 3: Endothelial USP2a is critical for pulmonary vascular remodeling in PH.
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Fig. 4: USP2a and METTL16 form a positive feedback loop in endothelial cells.
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Fig. 5: METTL16 mediates the USP2a-induced pro-migratory and pro-angiogenic effects on endothelial cells.
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Fig. 6: METTL16 enhances m6A-mediated IL-6R mRNA stabilization in endothelial cells.
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Fig. 7: USP2a inhibitor ML364 attenuates the MCT-PH in the rat model.
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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The raw datasets from RNA-seq and MeRIP-seq have been deposited in the GEO database under project accession numbers GSE295954/GSE295955. The raw dataset from TMT-based proteomics has been deposited in the PRIDE databases under project accession number PXD063478.

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Acknowledgements

We sincerely expressed our gratitude to Manghua Xu, Jian Li, Dengyu Wang, and Meichao Zhang from the North Central Laboratory of the Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine. Their conscientious management and kind assistance have enabled the safe and efficient completion of our work.

Funding

This work was supported by the project of the National Key R&D Program of China (2023YFC2307002 to HL), National Natural Science Foundation of China (82400061 to HZ, 82370057 to YP, 82103309 to WZ, 82201931 to JX, and 82271882 to HL), Natural Science Foundation of Shanghai (24ZR1460100 to JG), Science and Technology Commission of Shanghai Municipality (21DZ229800 to HL), Tongji University Medicine-X Interdisciplinary Research Initiative (2025-0554-ZD-05 to HL) and Department Support Fund of Shanghai Pulmonary Hospital (to JG).

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  1. These authors contributed equally: Hanqing Zhu, Ping Yuan.

Authors and Affiliations

  1. Department of Pulmonary Function Test, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

    Hanqing Zhu, Xingxing Sun, Jianhua Xu, Tianran Zhou, Wenlan Yang, Jinming Liu & Jian Guo

  2. Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

    Ping Yuan & Jinming Liu

  3. Innovation and Incubation Center, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

    Xiangyang Wu & Li Chen

  4. Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Guangzhou, China

    Yuxia Huang

  5. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China

    Wentian Zhang

  6. Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

    Junfang Xu & Haipeng Liu

  7. Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Tongji University School of Medicine, Shanghai, China

    Haipeng Liu

  8. Shanghai Engineering Research Center of Lung Transplantation, Shanghai, China

    Haipeng Liu

  9. Shanghai R&D Public Service Platform for Tuberculosis, Shanghai, China

    Haipeng Liu

  10. Department of Oncology, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Fenghou Gao

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  1. Hanqing Zhu
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Contributions

Conceptualization: HZ, JG, FG, and HL. Methodology: HZ, YP, JG, FG, and HL. Investigation: HZ, YP, YH, WZ, XS, JX, TZ, JX, and LC. Visualization: HZ, XW, and HL. Supervision: JG, FG, and HL. Writing—original draft: HZ, XW, WY, and JL. Writing—review and editing: JG, FG, and HL.

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Correspondence to Haipeng Liu, Fenghou Gao or Jian Guo.

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Zhu, H., Yuan, P., Wu, X. et al. Endothelial USP2a-METTL16 loop potentiates IL-6 signaling via m6A-mediated IL-6R stabilization in pulmonary vascular remodeling. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01747-0

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