PAK1/2 Signalling and Therapeutic Activation in Cardiac Protection

Yu He¹, James SH Bae¹ and Ming Lei¹

¹Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, United Kingdom

Corresponding to: Ming Lei (ming.lei@pharm.ox.ac.uk)

Over the past decade, work from our laboratories and others has established p21-activated kinases 1 and 2 (PAK1/2) as important regulators of cardiac homeostasis and potential therapeutic targets in cardiovascular disease. We have demonstrated that PAK1 plays a critical role in regulating ion channels, maintaining intracellular Ca²⁺ homeostasis and electrophysiological stability in the heart^1-6. Furthermore, activation of PAK1 signalling exerts cardioprotective effects against pathological hypertrophy, fibrosis, and ischaemia–reperfusion injury and heart failure ^1-7. More recently, we and others found that PAK2 is abundantly localised in close proximity to the endoplasmic reticulum (ER) membrane, where it acts as a key regulator of the IRE1/XBP1-dependent unfolded protein response (UPR), providing an additional mechanism of cardioprotection during cellular stress^{8, 9}.

Building on these mechanistic insights into PAK1/2-mediated cardioprotection, we have developed a novel peptide-guided strategy for discovery kinase activators. By identifying and targeting a previously unrecognised autoinhibitory interface between the PAK1/2 kinase domain (KD) and autoinhibitory domain (AID), we demonstrated that rational modulation of kinase autoinhibition can enhance PAK1/2 activity¹⁰. This approach has enabled the development of a series of potent small-molecule PAK1/2 activators and may provide a broadly applicable strategy for therapeutic kinase activator discovery—an area that remains substantially less explored. Importantly, these PAK1/2 activators exert robust antihypertrophic effects, attenuating cardiomyocyte hypertrophy and improving pathological myocardial remodelling¹⁰.

Collectively, our studies and those of others identify PAK1/2 as central regulators of Ca²⁺ homeostasis, electrophysiological stability, ER stress responses, and myocardial remodelling, supporting their development as novel therapeutic targets for cardiac hypertrophy, heart failure, and arrhythmias. By restoring Ca²⁺ homeostasis and modifying the arrhythmogenic substrate, pharmacological activation of PAK1/2 may offer a complementary therapeutic strategy to existing antiarrhythmic treatments. Further elucidation of the cellular and molecular mechanisms linking PAK1/2 activation to antihypertrophic and antiarrhythmic effects will be important for optimising these compounds and advancing PAK1/2-targeted therapies toward clinical translation.