PI3K/AKT/HIF-1α
PI3K/AKT/HIF-1α
Overview
PI3K/AKT/HIF-1α refers to a signaling axis linking phosphoinositide 3-kinase (PI3K), AKT, and hypoxia-inducible factor 1-alpha (HIF-1α). In biomedical research, this pathway is widely recognized as a central regulator of cell survival, metabolism, inflammatory responses, angiogenesis, and adaptation to hypoxic stress. PI3K and AKT are upstream signaling components that can promote HIF-1α stabilization and activity, thereby influencing downstream transcriptional programs involved in glycolysis, oxidative stress responses, and tissue remodeling.
Because of these functions, PI3K/AKT/HIF-1α is frequently studied in cancer, inflammatory disease, neuroinflammation, fibrosis, and metabolic disorders. Recent work has also connected this axis with related pathways such as PI3K/Akt signaling pathway, mTOR, PTEN, SIRT1/HIF-1α pathway, and Nrf-2-SLC7A11-GSH pathway, underscoring its role as an integrative node in disease-associated metabolic reprogramming and stress adaptation.
Focus of Latest Publications
Recent publications have continued to position PI3K/AKT/HIF-1α as a central immunometabolic signaling axis in inflammatory, fibrotic, and tumor-related disease models. In rheumatoid arthritis-associated interstitial lung disease, Glyasperin F was reported to upregulate Sirt1 and suppress PI3K/Akt/HIF-1α signaling, with downstream inhibition of glycolytic enzymes including HK2, PFK, PKM2, and LDHA, alongside reduced lactate and ATP production and oxidative stress. In this study, HIF-1α overexpression reversed the therapeutic effects, supporting a mechanistic link between pathway inhibition and the observed improvement in joint inflammation and pulmonary fibrosis.
Other recent work has examined HIF-1α-centered signaling in neuroinflammation and sepsis-associated encephalopathy. In a rat model of LPS-induced acute neuroinflammation, radiofrequency electromagnetic fields and pulsed magnetic fields were reported to attenuate neuroinflammation and demyelination via PI3K/AKT/HIF-1α-mediated neurovascular protection. In a separate sepsis-associated encephalopathy study, HIF-1α was shown to impair microglial efferocytosis through the SLC7A11-TAM axis; pharmacologic inhibition of HIF-1α with KC7F2 restored efferocytosis, improved inflammatory profiles, cognition, survival, and metabolomic signatures, whereas stabilization with DMOG had opposite effects.
The pathway has also been linked to obesity-associated adipose tissue remodeling. Single-nucleus RNA sequencing and spatial transcriptomics identified a disease-emergent adipocyte population with an end-of-trajectory signature (hEOS) in obese white adipose tissue, where HIF1A activation under hypoxic conditions was associated with increased LAMA4 expression. This LAMA4 signal was proposed to act through ITGB1 to promote NF-κB activation in a neighboring macrophage subset, and the activity of this axis correlated with BMI, HbA1c, and insulin resistance. Although this study did not directly target PI3K/AKT/HIF-1α, it reinforced HIF-1α as a key hypoxia-responsive node in metabolic inflammation.
Additional publications focused on HIF-1α-driven glycolysis in fibrotic and infectious settings. In liver fibrosis, a ROS/pH dual-responsive nanoparticle system delivered camptothecin to activated hepatic stellate cells and was reported to suppress HIF-1α-mediated glycolysis, thereby reducing proliferation, collagen deposition, and fibrotic progression. In vulvovaginal candidiasis, transcriptomics and molecular docking were used to investigate the N-butanol extract of Pulsatilla decoction in protecting vaginal epithelial cells against C. albicans infection through HIF-1α signaling and glucose metabolism. Collectively, these studies highlight PI3K/AKT/HIF-1α and related HIF-1α-centered pathways as recurring targets for modulating glycolysis, inflammation, and tissue remodeling across diverse disease models.