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Phosphoinositide 3-kinases (PI3Ks) play central roles in regulating critical cellular processes such as metabolism, cell survival, and motility, with their dysregulation implicated in cancer, inflammation, and metabolic disorders 1 , 2 , 3 . Of special interest is PI3K alpha (PI3Kα), a heterodimer of p110α and p85α. Cancer-specific mutations in p110α, such as H1047R, result in constitutive PI3Kα signaling, contributing to tumorigenesis by sustaining aberrant AKT-mTOR pathway 4 , 5 , 6 , 7 . While PI3K inhibitors have dominated therapeutic strategies for cancer and immune disorders, emerging evidence highlights the benefits of PI3Kα activation in tissue protection and regeneration 8 , 9 , 10 , 11 , 12 . For example, the small-molecule activator UCL-TRO-1938 (referred to as 1938 hereafter) selectively enhances PI3Kα activity, demonstrating cardioprotection against ischemia-reperfusion injury and promoting nerve regeneration in preclinical models 9 . Intriguingly, 1938 synergizes with H1047R to amplify PI3Kα activity, suggesting distinct yet complementary mechanisms that promote PI3Kα activation 9 . However, structural insights into how 1938 modulates PI3Kα conformations and cooperates with H1047R remain elusive.
Liu et al. (Fri,) studied this question.