Metabolic Reprogramming in Cardiac Fibrosis and Its Implications for Targeting PDK1

Cardiac fibrosis is driven by the activation of resident cardiac fibroblasts and their subsequent differentiation into myofibroblasts upon injury or stress. These activated myofibroblasts drive the fibrotic process through excessive secretion and deposition of extracellular matrix components, leading to adverse cardiac remodeling, tissue stiffening, and eventual functional impairment. Although myofibroblast formation serves as a physiological repair mechanism following acute injury, the sustained presence of these cells promotes maladaptive remodeling and gradual deterioration of cardiac function. In contrast to the well-characterized roles of transforming growth factor-β (TGF-β) and angiotensin II (AngII) signaling in fibrosis, the mitochondrial and metabolic reprogramming events essential for myofibroblast establishment and longevity remain comparatively understudied. 3-phosphoinositide-dependent protein kinase-1 (PDK1) is a master regulator of cellular energy metabolism and a key upstream activator of the AKT/mTOR axis; however, its specific role and therapeutic relevance in cardiac fibrosis remain elusive. Critically, although targeting the downstream AKT/mTOR pathway holds promise, the clinical translation of such inhibitors faces challenges including feedback activation and systemic toxicity. This review integrates current knowledge on metabolic and mitochondrial adaptations in cardiac fibrosis, with a focus on the potential involvement of PDK1. In support of this aim, our structural and computational analyses reveal a well-defined, ligandable ATP-binding pocket in PDK1 and demonstrate high-affinity binding of classical inhibitors, thereby structurally validating its potential as a druggable therapeutic target for mitigating fibrotic progression.