The synergistic inhibitory effect of PRKAA1 activation on ECM mechanical stress-induced skin fibrosis

Modulating mechanically mediated fibrosis to alleviate scar formation represents a critical frontier in current research. In previous fibrosis studies, metabolic reprogramming was largely viewed as a passive, secondary process. By combining biological experiments with multiomics analyses, our study reveals that pharmacological activation of AMP-activated catalytic subunit alpha1 ( PRKAA1/AMPKα1 ) affects mechanical signal transduction pathways and initiates regenerative metabolic rewiring. In dermal fibroblasts, elevated mechanical stress triggers a vicious cycle: insufficient PRKAA1 activation fails to supply adequate energy for YAP1 -driven fibrotic progression and increases the production of lactate and proinflammatory molecules. In this context, pharmacologically enhancing PRKAA1 activity results in a ​synergistic antifibrotic effect​ through two key mechanisms: First, PRKAA1 directly phosphorylates YAP1 to suppress hyperactive mechanical signaling, reducing the expression of fibrotic effector factors and thereby limiting their nuclear localization and transcriptional activity. Second, it reprograms cellular metabolism to fulfil the energy requirements for adapting to high stress, increasing the production of anti-inflammatory molecules and accelerating the synthesis of the extracellular matrix (ECM). This dual antifibrotic action rooted in PRKAA1 activity not only deepens our understanding of the regulatory role of metabolism in fibrosis but also offers a valuable translational framework for clinical scar management.