Nrp1 Signaling Reprograms Glutathione Metabolism to Drive Mitochondrial Dysfunction in Severe Asthma

Huang, Junwen; Zhao, Wenqu; Chen, Ying; Chen, Yaoxin; Gong, Zhaoqian; Ma, Yanyan; Li, Yuemao; Hu, Dapeng; Huang, Shuyu; Fan, Keke; Zhu, Bang; Peng, Xiaoqian; Peng, Xianru; Cai, Shaoxi; Zhao, Haijin

doi:10.3390/antiox15040463

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Nrp1 Signaling Reprograms Glutathione Metabolism to Drive Mitochondrial Dysfunction in Severe Asthma

by

Junwen Huang

^1,†

,

Wenqu Zhao

^1,†,

Ying Chen

¹,

Yaoxin Chen

¹,

Zhaoqian Gong

¹,

Yanyan Ma

¹,

Yuemao Li

¹,

Dapeng Hu

¹,

Shuyu Huang

¹,

Keke Fan

¹,

Bang Zhu

¹,

Xiaoqian Peng

¹,

Xianru Peng

²,

Shaoxi Cai

^1,* and

Haijin Zhao

^1,*

¹

Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

²

Department of Respiratory and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Antioxidants 2026, 15(4), 463; https://doi.org/10.3390/antiox15040463

Submission received: 22 February 2026 / Revised: 22 March 2026 / Accepted: 25 March 2026 / Published: 8 April 2026

(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)

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Abstract

Mitochondrial dysfunction drives persistent inflammation in severe asthma, yet its upstream metabolic regulation remains unclear. Induced sputum from patients with severe asthma was analyzed and integrated with transcriptomic datasets from independent cohorts. Two mouse models (C57BL/6J) were used for in vivo validation with multi-omics profiling, and mechanistic studies were performed in air–liquid interface-cultured primary human airway epithelial cells. Glutathione reduced form (GSHr) was markedly depleted in sputum and associated with poor disease control and mixed granulocytic inflammation in patients with severe asthma. Multi-omics analyses revealed coordinated disruption of glutathione (GSH) metabolism, including oxidized GSH accumulation, reduced synthesis and glutathione-S-transferase activity, and impaired mitochondrial GSH transport. GSH supplementation alleviated airway inflammation, oxidative stress, and mitochondrial dysfunction, whereas pharmacological inhibition of GST exacerbated these effects. Mitochondrial analyses identified suppressed SLC25A39 expression as a key mediator of defective GSH transport and redox imbalance. Transcriptomic profiling of airway biopsies showed upregulation of Neuropilin-1 (Nrp1), closely associated with altered glutathione pathways. Targeting the Nrp1 b1 domain restored mitochondrial GSH metabolism and attenuated airway inflammation. These findings identify an Nrp-centered metabolic pathway that disrupts mitochondrial homeostasis and drives inflammatory amplification, highlighting mitochondria-targeted therapeutic strategies for severe asthma.

Keywords: severe asthma; glutathione metabolism; mitochondrial dysfunction; SLC25A39; Neuropilin-1

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MDPI and ACS Style

Huang, J.; Zhao, W.; Chen, Y.; Chen, Y.; Gong, Z.; Ma, Y.; Li, Y.; Hu, D.; Huang, S.; Fan, K.; et al. Nrp1 Signaling Reprograms Glutathione Metabolism to Drive Mitochondrial Dysfunction in Severe Asthma. Antioxidants 2026, 15, 463. https://doi.org/10.3390/antiox15040463

AMA Style

Huang J, Zhao W, Chen Y, Chen Y, Gong Z, Ma Y, Li Y, Hu D, Huang S, Fan K, et al. Nrp1 Signaling Reprograms Glutathione Metabolism to Drive Mitochondrial Dysfunction in Severe Asthma. Antioxidants. 2026; 15(4):463. https://doi.org/10.3390/antiox15040463

Chicago/Turabian Style

Huang, Junwen, Wenqu Zhao, Ying Chen, Yaoxin Chen, Zhaoqian Gong, Yanyan Ma, Yuemao Li, Dapeng Hu, Shuyu Huang, Keke Fan, and et al. 2026. "Nrp1 Signaling Reprograms Glutathione Metabolism to Drive Mitochondrial Dysfunction in Severe Asthma" Antioxidants 15, no. 4: 463. https://doi.org/10.3390/antiox15040463

APA Style

Huang, J., Zhao, W., Chen, Y., Chen, Y., Gong, Z., Ma, Y., Li, Y., Hu, D., Huang, S., Fan, K., Zhu, B., Peng, X., Peng, X., Cai, S., & Zhao, H. (2026). Nrp1 Signaling Reprograms Glutathione Metabolism to Drive Mitochondrial Dysfunction in Severe Asthma. Antioxidants, 15(4), 463. https://doi.org/10.3390/antiox15040463

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Nrp1 Signaling Reprograms Glutathione Metabolism to Drive Mitochondrial Dysfunction in Severe Asthma

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