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.
Key Publications
- Jun Activation of Sirt1 by Glyasperin F Suppresses PI3K/Akt/HIF-1α Signaling and Inhibits Glycolytic Metabolism to Ameliorate Pathology in Rheumatoid Arthritis-Associated Interstitial Lung Disease. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42216775): "HIF-1α overexpression reversed these therapeutic effects."
- May Radiofrequency and pulsed magnetic fields attenuate LPS-induced neuroinflammation and demyelination via PI3K/AKT/HIF-1α-mediated neurovascular protection. (Molecular biology reports, 2026, PMID 42183935): "...attenuate LPS-induced neuroinflammation and demyelination via PI3K/AKT/HIF-1α-mediated neurovascular protection."
- May A transcriptionally distinct population of human adipocytes with end-of-trajectory signature (hEOS) emerges during obesity to drive maladaptive inflammation. (Pharmacological research, 2026, PMID 42107509): "Mechanistically, HIF1A activation in hEOS under hypoxic conditions is associated with increased expression of the extracellular matrix protein LAMA4, which contribute to niche remodeling and is spatially associated with Mac3 macrophages."
- Jun Targeting HIF-1α rescues microglial efferocytosis via the SLC7A11-TAM pathway to ameliorate Sepsis-associated encephalopathy. (International immunopharmacology, 2026, PMID 41990706): "This work uncovers a previously unknown HIF-1α-SLC7A11 pathway driving microglial dysfunction in SAE, offering fresh insight into disease mechanisms and pointing to HIF-1α as a promising therapeutic target."
- Mar Dunhuang Daxiefei Decoction ameliorates acute lung injury via the HIF-1α/glycolysis/H3K18la axis. (Journal of ethnopharmacology, 2026, PMID 41903585): "HIF-1α- driven glycolysis can promote histone lactylation and sustain pro-inflammatory (M1) macrophage responses."
- Mar Bie-Jia-Jian Pill: Inhibiting tumor glycolysis and promoting CD8+ cell-mediated anti-tumor immunity by targeting HIF-1α-PI3K/AKT/mTOR and CCL20 in hepatocellular carcinoma. (Journal of ethnopharmacology, 2026, PMID 41866005): "Bie-Jia-Jian Pill: Inhibiting tumor glycolysis and promoting CD8+ cell-mediated anti-tumor immunity by targeting HIF-1α-PI3K/AKT/mTOR and CCL20 in hepatocellular carcinoma."
- Jun Mechanism of N-butanol extract of Pulsatilla decoction protected vaginal epithelial cells against Candida albicans infection by HIF-1α signaling and glucose metabolism revealed by transcriptomics and molecular docking. (Journal of ethnopharmacology, 2026, PMID 41825727): "Mechanism of N-butanol extract of Pulsatilla decoction protected vaginal epithelial cells against Candida albicans infection by HIF-1α signaling and glucose metabolism revealed by transcriptomics and molecular docking."
- Mar Metal-phenolic nanoparticles with ROS/pH dual-responsiveness for liver fibrosis therapy via synergistic microenvironment remodeling and metabolic reprogramming. (Colloids and surfaces. B, Biointerfaces, 2026, PMID 41819037): "Notably, the released CPT reduces energy supply by inhibiting HIF-1α-mediated glycolysis, thereby effectively suppressing the proliferation of activated HSCs."