Fibrinogen-like protein 2 regulates inflammatory and metabolic reprogramming of airway smooth muscle cells through PI3K/Akt activation

Background Fibrinogen-like protein 2 (FGL2) participates in inflammatory and immune regulation; however, its contribution to airway smooth muscle cell (ASMC) dysfunction remains poorly defined. This study investigated the role of FGL2 in platelet-derived growth factor-BB (PDGF-BB)-induced pathological responses in ASMCs and explored the underlying signaling mechanisms. Methods Human ASMCs were transfected with FGL2-specific small interfering RNA (si-FGL2) or negative control siRNA (si-NC) and subsequently stimulated with PDGF-BB, with or without the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway activator insulin-like growth factor-1 (IGF-1). Activation of the PI3K/Akt signaling, ASMC proliferation and migration, extracellular matrix (ECM) protein expression, inflammatory cytokine production, oxidative stress and antioxidant capacity, and glycolytic metabolism were systematically assessed using molecular and biochemical approaches. Results PDGF-BB stimulation markedly increased FGL2 expression in ASMCs. Silencing FGL2 significantly attenuated PDGF-BB-induced PI3K/Akt activation, as indicated by reduced phosphorylation of PI3K and Akt. FGL2 knockdown suppressed ASMC proliferation, migration, and ECM protein expression, including collagen I, α -smooth muscle actin, and fibronectin. In addition, FGL2 depletion significantly reduced the expression and secretion of proinflammatory cytokines (TNF- α , IL-1β, and IL-6), decreased intracellular reactive oxygen species accumulation and lipid peroxidation, and restored the activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase. Furthermore, glycolytic reprogramming induced by PDGF-BB-reflected by increased glucose consumption, lactate production, ATP generation, and upregulation of pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), was markedly inhibited by FGL2 knockdown. Pharmacological reactivation of PI3K/Akt signaling with IGF-1 partially reversed these inhibitory effects. Conclusion These findings suggest that FGL2 may contribute to PDGF-BB-induced ASMC dysfunction, including enhanced proliferation, migration, inflammation, oxidative stress, and glycolytic reprogramming, potentially by modulating the PI3K/Akt signaling pathway. Although preliminary, these results indicate that FGL2 could represent a potential therapeutic target for limiting airway remodeling in chronic airway diseases and warrant further investigation.