Brain aging is accompanied by progressive glial dysfunction, impaired metabolic adaptation, oxidative stress, and increased susceptibility to neurodegenerative disease. Although many studies of lipid metabolism in aging and neurodegeneration emphasize lipid abundance, lipid amount alone cannot explain why glia become redox-vulnerable. This review advances a chemistry-resolved integrative framework in which glial lipid reprogramming is understood through aging- and disease-associated changes in lipid identity, composition, oxidation state, storage form, subcellular localization, and lipid-mediated signaling. We discuss evidence from aged brain tissue, human neurodegenerative disease, iPSC-derived glial systems, and mouse models showing that altered lipid handling in microglia, astrocytes, and oligodendrocyte-lineage cells reshapes phagocytosis, inflammatory signaling, myelin processing, astrocytic metabolic support, and neuronal injury. We emphasize that acyl-chain saturation, head-group structure, oxidized lipid species, neutral lipid storage, plasmalogen-dependent redox buffering, peroxisomal lipid metabolism, and compartmental distribution determine how lipids regulate receptor engagement, lipid-droplet dynamics, lysosomal stress, mitochondrial function, ferroptotic susceptibility, and inflammatory redox signaling. Importantly, glial lipid reprogramming is further shaped by extracellular vesicle-mediated neuron-glia communication, regional lipid heterogeneity, and sex-dependent modifiers of glial metabolism. Oxidative stress therefore reflects the convergence of polyunsaturated fatty acid (PUFA)-enriched membranes, oxidized phospholipids, oxysterols, ceramide accumulation, plasmalogen loss, mitochondrial reactive oxygen species (ROS) production, lysosomal iron release, peroxisomal dysfunction, and declining glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), GTP cyclohydrolase 1-tetrahydrobiopterin (GCH1-BH4), and nuclear factor erythroid 2-related factor 2 (NRF2)-dependent protective systems. Finally, we discuss lipid-centered therapeutic opportunities targeting cholesterol efflux, apolipoprotein E (APOE) lipidation, lipid-droplet metabolism, sphingolipid pathways, lipid peroxide defense, plasmalogen support, extracellular vesicle biology, and lipid-based delivery systems. By shifting the focus from lipid accumulation to lipid identity, compartmental handling, and biological context, this review synthesizes glial lipid reprogramming as an integrative framework linking brain aging to redox-sensitive neurodegeneration.
Aims Pulmonary hypertension (PH), a severe vascular disorder, is closely associated with chronic inflammatory states and oxidative stress. Myeloid differentiation protein 2 (MD2), a key co-receptor of Toll-like receptor 4 (TLR4), is well established in mediating various inflammation-driven pathologies. However, its role in pulmonary hypertension and its potential involvement in oxidative stress regulation remain unclear. Methods and results MD2 expression was upregulated in both PH patients and murine PH models. Genetic or pharmacological inhibition of MD2 improved hemodynamic parameters, attenuated pulmonary vascular remodeling, and reduced right ventricular hypertrophy. MD2 inhibition significantly reduced mitochondrial oxidative stress in vivo and in vitro. Mechanistic studies demonstrated that suppression of the membrane protein MD2 activated intracellular AMP-activated protein kinase (AMPK) signaling, leading to enhanced peroxisome proliferator-activated receptor γ (PPARγ) activity. PPARγ, in turn, suppressed nuclear transcription of NADPH oxidase 4 (NOX4), resulting in a marked reduction in mitochondrial oxidative stress. Conclusion This study indicates that MD2 may act as an upstream regulator of mitochondrial oxidative stress in PH. Inhibition of MD2 attenuates pulmonary hypertension through activation of the AMPK/PPARγ axis, which suppresses NOX4 mediated mitochondrial oxidative stress. Targeting MD2 may represent a novel therapeutic strategy for PH.
Triple-negative breast cancer (TNBC) remains a highly aggressive malignancy with limited responsiveness to immune checkpoint blockade. Here, we identify endoplasmic reticulum oxidoreductase 1 alpha (ERO1α; ERO1A), a key regulator of oxidative protein folding, as a determinant of tumor immunogenicity and immunotherapy response in TNBC. Unbiased proteomic profiling demonstrated that ERO1α deficiency remodels the TNBC glycoproteome, leading to enrichment of pathways associated with immune signaling. Although ERO1α loss did not affect tumor cell growth, it reshaped the immune tumor microenvironment, enhancing antigen presentation, altering myeloid-cell composition, and modulating PD-1/PD-L1–associated signaling.Functionally, ERO1α deficiency sensitized otherwise refractory TNBC tumors to PD-1 blockade, resulting in durable tumor regression in immunocompetent hosts. In contrast, ERO1α deletion in bone marrow–derived immune cells had minimal effects on tumor growth or therapeutic response, supporting an ERO1α tumor-intrinsic mechanism. Pharmacologic inhibition of ERO1α with the novel small-molecule inhibitor I29 phenocopied ERO1α genetic deletion and enhanced the efficacy of anti–PD-1 therapy. Together, these findings identify ERO1α-dependent glycoproteome remodeling as a regulator of antitumor immunity and a therapeutically actionable mechanism of immune checkpoint responsiveness in TNBC.
