SIRT1 deacetylates GAPDH to drive microglial glycolysis and neuroinflammation

Glycogen-Dependent Metabolic Reprogramming Regulates Microglial Activation and Dysfunction in Neurodegenerative Disease

Microglia are central regulators of neuroinflammation in Alzheimer’s disease (AD), yet how metabolic states modulate function remains unclear. Here we show that microglia from the APPNL-G-F mouse model revealed upregulation of glycolytic enzymes coinciding with onset of microglial activation. Surprisingly, this glycolytic shift occurred alongside reduced expression of glucose transporters, suggesting that extracellular glucose may not be the primary fuel source, implicating glycogenolysis as the potential metabolic driver. Consistent with this, significant microglial glycogen accumulation was noted in late disease, when cells exhibited features of metabolic exhaustion and functional impairment. Pharmacological inhibition of glycogenolysis blunted microglia responses to Abeta aggregates and markedly reduced Abeta uptake, confirming a functional role for glycogen metabolism in shaping microglial states. Together, these findings identify glycogen as a central regulator of microglial metabolic health and function, highlighting glycogen homeostasis as a potential therapeutic target for promoting Abeta clearance and preserving protective microglial functions in AD.

AMPKγ2 Deacetylation Drives Nuclear Translocation and Doxorubicin-Induced Cardiomyopathy via Nucleolar Stress Signaling

Doxorubicin (Dox)-induced cardiomyopathy (DIC), characterized by cardiomyocyte apoptosis, remains a major clinical challenge in chemotherapy. The regulatory γ2 subunit of AMP-activated protein kinase (AMPKγ2) plays a key role in cardiovascular diseases, but its function in DIC is poorly understood. Here, we report that Dox induces isoform-specific deacetylation and nuclear accumulation of γ2, triggering nucleolar stress and p53-mediated apoptosis. Mechanistically, HDAC3 and TIP60 interact with γ2 and modulate the acetylation of multiple lysine residues within its nuclear localization signal (NLS), controlling its nucleocytoplasmic shuttling. Dox enhances HDAC3-mediated γ2 deacetylation, thereby driving nuclear accumulation of the γ2-containing AMPK (γ2-AMPK) while suppressing the cytosolic AMPK activity. Nuclear γ2-AMPK phosphorylates and inactivates TIF-IA, a key RNA polymerase I-specific transcription initiation factor, leading to nucleolar stress through inhibition of rRNA transcription. rRNA deficit triggers release of free ribosomal proteins (RPs), which bind to and inhibit the E3 ubiquitin ligase MDM2, resulting in p53 stabilization and activation of apoptotic signaling. Using genetically engineered cardiomyocytes and a DIC mouse model, we found that a deacetyl-mimetic γ2 mutant (6KR) exacerbated DIC, whereas an acetyl-mimetic mutant (6KQ) was cardioprotective. Collectively, our findings establish acetylation-driven nuclear translocation of γ2 as a critical node linking Dox-induced nucleolar stress to p53-dependent apoptosis and suggest a promising cardio-oncology strategy that combines HDAC inhibitors with Dox to mitigate DIC. Significance statement Doxorubicin is an effective cancer drug, but its use is limited by cardiomyopathy. Our study reveals that doxorubicin drives HDAC3-mediated deacetylation of AMPKγ2, exposing its nuclear localization signal and redirecting γ2-containing AMPK from the cytoplasm to the nucleus. Nuclear AMPKγ2 phosphorylates TIF-IA, suppresses ribosomal RNA synthesis, and activates a nucleolar stress pathway that stabilizes p53 and promotes cardiomyocyte apoptosis. In mice, a deacetylation-mimetic AMPKγ2 mutant worsens doxorubicin-induced cardiomyopathy, whereas an acetylation-mimetic mutant is protective. These findings uncover an acetylation-controlled spatial switch in AMPK signaling and identify the AMPKγ2 deacetylation–nucleolar stress axis as a potential target for reducing chemotherapy-associated cardiac injury.

Deciphering the role of sirtuins in cancer immunoregulation through molecular cross-talk and docking-based interaction

SIRT Family: Biological Functions and Therapeutic Targets

Sirtuins (SIRT1–SIRT7) are nicotinamide adenine dinucleotide (NAD+) dependent deacylases that serves as metabolic sensors, coupling cellular energy status to chromatin structure, mitochondrial function, and stress responses. Dysregulated SIRT activity has been extensively studied in aging, metabolic syndrome, cardiovascular disease, neurodegeneration, cancer, and immune disorders. However, robust human evidence and SIRT‐targeted therapies are lacking. Transgenic mouse models serve as key platforms to study gene function and guide therapeutic development. This review synthesizes evidence from Sirt1–7 transgenic mouse models regarding the core cellular processes governed by SIRTs: metabolism, genome integrity, stress resistance, immunity, and autophagy, and illustrates their operation across different organ systems. By comparing global, tissue‐specific, and inducible knockout (KO) and overexpression (OE) models of cardiovascular, respiratory, digestive, nervous, endocrine, urogenital, musculoskeletal, malignant, and immune diseases, we identified central regulatory SIRTs (SIRT1, SIRT3, and SIRT6), context‐dependent modifiers (SIRT2, SIRT4, SIRT5, and SIRT7), and their organ‐ and cell type‐specific functions. We also summarize representative small‐molecule SIRT activators, inhibitors, and degraders, covering both clinical and preclinical studies, and highlight where contradictions and knowledge gaps remain. Together, these analyses help clarify which aspects of SIRT modulation are most promising and under what isoform, tissue, and disease contexts they should be pursued for the development of SIRT‑targeted therapies in human disease.

Opioids Promote Autophagy and Attenuate LPS-Induced Cellular Senescence-Associated Changes in Microglia

: Background: Opioids can modulate mitochondrial redox homeostasis and autophagy and are implicated in the regulation of key physiological and pathological processes, including aging, cellular metabolism, and tumorigenesis. The study aimed to investigate how opioid receptor agonists influence lipopolysaccharide-induced senescence in microglia. Methods: C8-B4 microglial cells were either left untreated or pretreated with different opioid agonists and subsequently exposed to lipopolysaccharide (LPS). Colorimetric assays, fluorescence microscopy, flow cytometry, and Western blotting were used to assess cellular senescence, autophagy-associated changes, reactive oxygen species, and calcium levels, as well as the expression of selected marker proteins and signaling molecules. Results: Treatment with DAMGO, DADLE, and U-50488 significantly attenuated LPS-induced increases in intracellular calcium levels and reduced the expression of cellular senescence markers, including p53, p16, p21, SA-β -Gal activity, and mitochondrial ROS (mtROS), while enhancing total antioxidant capacity ( p < 0.05). Notably, opioid treatment was associated with changes consistent with increased autophagy-related activity, as demonstrated by the upregulation of autophagy-related markers Autophagy-related proteins 5 and 7, beclin-1, and microtubule-associated proteins 1A/1B light chain 3B (MAP-LC3). It reversed LPS-induced impairment of autophagy-related activity, evidenced by increased degradation of p62 ( p < 0.05). Furthermore, opioids inhibited LPS-induced activation of the phosphatidylinositol 3-kinase/Protein Kinase B/mechanistic Target of Rapamycin signaling pathway ( p < 0.05), thereby promoting autophagy. Conclusions: Taken together, these findings suggest that opioids may support cell survival, attenuate LPS-associated senescence markers, and be accompanied by changes consistent with increased autophagy-related activity.

CCR5 drives glucose metabolic reprogramming to control microglial synaptic pruning via histone lactylation in a mouse model of depression.

Depression is linked to microglial activation, but the precise triggers and downstream pathways remain elusive. Through single-cell RNA sequencing of human blood samples, we find upregulation of the CCL5-CCR5 axis in patients with major depressive disorder. Using a chronic social defeat stress mouse model, we show that CCR5 is specifically elevated in activated hippocampal microglia. Microglia-specific deletion of CCR5 alleviates depressive-like behaviors and prevents microglial activation. Mechanistically, CCR5 binding to VHL stabilizes HIF-1α, redirecting microglial metabolism toward aerobic glycolysis. This metabolic shift results in lactate accumulation, which drives histone H4 lysine 12 lactylation (H4K12la). Genome-wide profiling reveals that H4K12la enrichment at complement gene promoters facilitates their transcription, ultimately leading to excessive microglial engulfment of neuronal spines and synaptic loss. Importantly, either inhibiting glycolysis or exogenous lactate supplementation can respectively rescue or mimic the pathological synaptic pruning and depressive-like behaviors. Our findings indicate a CCR5-driven immune-metabolic-transcriptional axis in microglia that underlies synaptic deficits in depressive-like behaviors, offering potential targets for therapeutic intervention.