A Novel Pak1 Activator Ameliorates ER Stress for HFpEF Therapy
7 affiliations
- 1Division of Cardiovascular Science, Faculty of Biology, Medicine and Health The University of Manchester Manchester UK
- 2Department of Internal Medicine III University of Kiel Kiel Germany
- 3German Center for Cardiovascular Research (DZHK) Partner Site Hamburg/Kiel/Luebeck Hamburg Germany
- 4Division of Molecular and Cellular Function, School of Biological Sciences The University of Manchester Manchester UK
- 5Department of Pharmacology University of Oxford Oxford UK
- 6Department of Surgery Baylor College of Medicine Houston USA
- 7Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing China
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a prevalent and complex syndrome, with metabolic dysfunction playing a pivotal role in its progression. Disrupted endoplasmic reticulum (ER) homeostasis is recognized as a central mechanism in its pathogenesis. Although the homologous kinases Pak1 and Pak2 regulate the ER stress response, the role of Pak1 in HFpEF remains unclear. This study demonstrates that Pak1 is a critical regulator of cardiac adaptation to metabolic stress. Using a murine HFpEF model combining high‑fat diet and nitric oxide synthase inhibition, Pak1 knockdown accelerates diastolic dysfunction and maladaptive remodeling, accompanied by disrupted ER ultrastructure and impaired PERK‑ATF4 signaling, whereas Pak1 overexpression preserves cardiac function and ER homeostasis. Mechanistically, Pak1 activates the ERK1/2‐MNK1‐eIF4E signaling axis and promotes adaptive integrated stress response (ISR) signaling through the PERK‐ATF4 pathway. Pharmacological inhibition of MNK1 attenuated Pak1‐mediated PERK activation and ATF4 induction, identifying a mechanistic link between Pak1 signaling and adaptive stress responses. Furthermore, we developed a novel small‐molecule Pak1 activator, JB2019, which reversed metabolic stress‐induced cardiac dysfunction in both HFpEF mice and cardiac organoids. Collectively, these findings identify Pak1 as a novel regulator of adaptive ISR signaling and establish Pak1 activation as a promising therapeutic strategy for HFpEF.
Related
- Discovery of a Small-Molecule mTORC1 Pathway Activator that Enhances Adoptive T-Cell Therapy via Immuno-metabolic Reprogramming of CD8+ T Cells
- A novel KIR3DL2-directed CAR T-cell therapy for cutaneous and systemic T-cell lymphomas
- Morphological and biochemical evaluation of tolerance to water deficit identifies SlCLE9 as a novel regulator of drought stress
- Retinal Structural and Microvascular Findings During Novel NPR-B-Targeted Vosoritide Therapy in Children with Achondroplasia
- Stress adaptation of free-living microbes generates novel benefits to plant hosts
BibTeX
@article{xu2026novel,
title = {{A Novel Pak1 Activator Ameliorates ER Stress for HFpEF Therapy}},
author = {Honglin Xu and Hongyuan Zhang and Tayyiba Azam and Susanne S. Hille and Yingjuan Liu and Min Zi and Jiaqing Lang and He Yu and Yujia Cao and Bernard D. Keavney and Tamer M. A. Mohamed and Jessica M. Miller and Riham R. E. Abouleisa and Ming Xu and Elizabeth J. Cartwright and Oliver J. Müller and Ming Lei and Xin Wang},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.76964},
url = {https://doi.org/10.1002/advs.76964},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A Novel Pak1 Activator Ameliorates ER Stress for HFpEF Therapy
AU - Honglin Xu
AU - Hongyuan Zhang
AU - Tayyiba Azam
AU - Susanne S. Hille
AU - Yingjuan Liu
AU - Min Zi
AU - Jiaqing Lang
AU - He Yu
AU - Yujia Cao
AU - Bernard D. Keavney
AU - Tamer M. A. Mohamed
AU - Jessica M. Miller
AU - Riham R. E. Abouleisa
AU - Ming Xu
AU - Elizabeth J. Cartwright
AU - Oliver J. Müller
AU - Ming Lei
AU - Xin Wang
PY - 2026
DA - 2026/08/03
JO - Advanced Science
DO - 10.1002/advs.76964
UR - https://doi.org/10.1002/advs.76964
AB - Heart failure with preserved ejection fraction (HFpEF) is a prevalent and complex syndrome, with metabolic dysfunction playing a pivotal role in its progression. Disrupted endoplasmic reticulum (ER) homeostasis is recognized as a central mechanism in its pathogenesis. Although the homologous kinases Pak1 and Pak2 regulate the ER stress response, the role of Pak1 in HFpEF remains unclear. This study demonstrates that Pak1 is a critical regulator of cardiac adaptation to metabolic stress. Using a murine HFpEF model combining high‑fat diet and nitric oxide synthase inhibition, Pak1 knockdown accelerates diastolic dysfunction and maladaptive remodeling, accompanied by disrupted ER ultrastructure and impaired PERK‑ATF4 signaling, whereas Pak1 overexpression preserves cardiac function and ER homeostasis. Mechanistically, Pak1 activates the ERK1/2‐MNK1‐eIF4E signaling axis and promotes adaptive integrated stress response (ISR) signaling through the PERK‐ATF4 pathway. Pharmacological inhibition of MNK1 attenuated Pak1‐mediated PERK activation and ATF4 induction, identifying a mechanistic link between Pak1 signaling and adaptive stress responses. Furthermore, we developed a novel small‐molecule Pak1 activator, JB2019, which reversed metabolic stress‐induced cardiac dysfunction in both HFpEF mice and cardiac organoids. Collectively, these findings identify Pak1 as a novel regulator of adaptive ISR signaling and establish Pak1 activation as a promising therapeutic strategy for HFpEF.
SN - 2198-3844
ER -