A Novel Pak1 Activator Ameliorates ER Stress for HFpEF Therapy.

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.