Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease with a poor prognosis and limited therapeutic options. Current antifibrotic therapies only slow disease progression, underscoring an urgent need for novel therapeutic strategies. In recent years, metabolic reprogramming, notably the shift towards aerobic glycolysis (the Warburg effect), has emerged as a key driver of PF pathogenesis. This review comprehensively examines the central role of glycolysis in fueling the fibrotic cascade. It summarizes the major risk factors and fundamental pathogenic mechanisms of PF. The review then delves into the molecular mechanisms by which profibrotic signals, such as TGF‑β1, remodel cellular metabolism. The upregulation and pathogenic roles of critical glycolytic nodes are detailed‑including glucose transporters, hexokinase 2, phosphofructokinase‑2/fructose‑2,6‑bisphosphatase 3, pyruvate kinase M2 and lactate dehydrogenase A‑in activated fibroblasts, injured epithelial cells and pro‑fibrotic immune cells. Furthermore, the interplay between glycolysis and key signaling pathways (TGF‑β1, hypoxia‑inducible factor‑1α, PI3K/AKT/mTOR, Hippo, AMP‑activated protein kinase and sirtuins) that form feed‑forward loops to sustain the fibrotic process is discussed. Furthermore, therapeutic strategies targeting glycolytic enzymes and upstream metabolic checkpoints are highlighted, summarizing preclinical evidence for small‑molecule inhibitors and non‑coding RNAs as emerging regulators of glycolytic reprogramming. By consolidating current knowledge on glycolysis‑centric metabolic underpinnings of PF, this review underscores the promise of metabolism‑based interventions and discusses challenges for translating these findings into effective therapies.
