bims-microg 2026-03-22 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–03–22
fifteen papers selected by
Marcus Karlstetter, Universität zu Köln

NFAT1+ microglia promote antiinflammatory polarization and angiogenesis via the HAS3-HA-LYVE1 axis to improve ischemic stroke outcomes.
AXIS of excitability: microglia promote neuronal firing.
Glioma-induced DNMT3A reduction in microglia promotes an anti-tumoral phenotype.
Spatially Resolved Opto-Omics Uncovers Functional Microglial Subtypes in Brain Metastasis.
Distinct origins and niches determine the cellular responsiveness of CNS macrophages after repopulation.
OGG1 modulates the crosstalk of microglia and Müller cells in degenerative retinas via alleviating inflammatory response and oxidative stress.
Blocking microglial reactivity via purinergic receptors prevents subacute cognitive deficits after TIA.
Microglial fructose metabolism is essential for glioblastoma growth.
From chronic pain to depression: Neurogenesis-driven microglial remodeling in the hippocampal dentate gyrus.
Microglial NLRP3-dependent pyroptosis promotes cognitive dysfunction of diabetic encephalopathy by inhibiting adult hippocampal neurogenesis through the release of IL-1β.
Fe-Doped Carbon Dots Functionalized Nanoelectrode for In Situ Monitoring of Metabolism-Associated ROS Changes in Single Microglia.
Microglia-independent rAAV-induced inflammation causes persistent ocular immune dysregulation rescued by S1P receptor modulation.
Myeloid HDAC3 deletion protects against traumatic optic injury.
SLC22A3 deficiency leads to cognitive impairment through the cardio-neuroinflammatory axis mediated HA/H1R/NLRP3 pathway in heart failure mice.
A BBB-Penetrating Fullerene Mediates Recovery from Intracerebral Hemorrhage via Dually Promoting Hematoma Clearance and Neuroprotection.

Cell Mol Biol Lett. 2026 Mar 18.

NFAT1+ microglia promote antiinflammatory polarization and angiogenesis via the HAS3-HA-LYVE1 axis to improve ischemic stroke outcomes.

Yaochuan Zhang, Xu Cao, Yifu Song, Xiaodi Han, Guofeng Tian, Dongxia Tao, Ana Hou, Sheng Han.

   BACKGROUND: Neuroinflammation and angiogenesis are central to post-stroke repair. However, the cellular and molecular mechanisms regulating these events remain incompletely understood. The nuclear factor of activated T cells-1 (NFAT1) is implicated in inflammation and vascular remodeling, yet its role in ischemic stroke is unclear.
METHODS: We established Nfat1-deficient (Nfat1-/-) and Nfat1+/+ stroke mice to investigate the role of NFAT1 in post-stroke inflammation and repair. Neurological outcomes, infarct volume, neuronal injury, synaptic protein expression, neuroinflammation, angiogenesis, and cerebral blood flow were assessed by behavioral test, magnetic resonance imaging (MRI), Nissl staining, western blotting, ELISA, immunofluorescence, and laser speckle imaging, respectively. ChIP, dual-luciferase, and mechanistic assays identified NFAT1 downstream targets and signaling pathways. Conditioned medium experiments examined the impact of Nfat1+/+ primary microglia on endothelial cell behavior. NFAT1-overexpressing microglia were transplanted to assess therapeutic efficacy in vivo.
RESULTS: Nfat1-/- stroke mice showed worsened neurological function, increased neuronal damage, and reduced expression of antiinflammatory and proangiogenic factors (interleukin (IL)-10, tumor growth factor (TGF)-β, VEGFA, and FGF2). NFAT1 deficiency impaired microglial polarization (CD163+ and CD206+), angiogenesis, and blood perfusion. NFAT1 upregulated HAS3 and LYVE1, promoting HA-LYVE1 autocrine/paracrine signaling and activation of the Wnt/β-catenin pathway, which facilitated antiinflammatory polarization. Conditioned medium experiments confirmed that Nfat1+/+ microglia enhanced endothelial cell proliferation, migration, and tube formation. NFAT1-overexpressing microglia therapy enhanced antiinflammatory responses and angiogenesis, improved neurological recovery (e.g. Garcia score at day 35 increased by 0.87 points versus control), and reduced infarct size (corrected infarct area decreased by 27.29 units) in stroke mice.
CONCLUSIONS: Microglial NFAT1 drives antiinflammatory polarization and angiogenesis via the HAS3-HA-LYVE1-Wnt/β-catenin axis, ultimately improving stroke recovery. These findings reveal a previously unrecognized mechanism of neurovascular repair and highlight NFAT1+ microglia as a promising therapeutic target for ischemic stroke.

Keywords:  Angiogenesis; Cell therapy; HAS3; Ischemic stroke; LYVE1; Microglia; NFAT1; Neuroinflammation; Wnt/β-catenin

DOI:  https://doi.org/10.1186/s11658-026-00906-y
Cell Res. 2026 Mar 19.

AXIS of excitability: microglia promote neuronal firing.

Victoria L Palfini, Matthew N Rasband.

DOI: https://doi.org/10.1038/s41422-026-01237-5
Cell Death Differ. 2026 Mar 18.

Glioma-induced DNMT3A reduction in microglia promotes an anti-tumoral phenotype.

Mathilde Cheray, Mercedes Posada-Pérez, Adamantia Fragkopoulou, Carlos F D Rodrigues, Adriana-Natalia Murgoci, Ahmed M Osman, Guillermo Vázquez-Cabrera, Martin Škandík, Christine C Hong, Pinelopi Engskog-Vlachos, Shigeaki Kanatani, Yue Li, Stefan Spulber, Lara Friess, Theodora Sylaidi, Marie-Kim St-Pierre, Lena-Maria Carlson, Anastasios Damdimopoulos, Per Uhlén, Fredrik Kamme, Klas Blomgren, Bertrand Joseph.

Glioblastoma, IDH1 wildtype, aggressive primary brain tumors with a dismal prognosis, promote the recruitment of microglia, brain resident innate immune cells, and ultimately their activation toward a tumor-supportive phenotype that increases gliomal proliferation and invasion capability. Here, we report that upon stimulation by glioma cells, microglia transit via a reactive state holding anti-tumoral properties coupled to reduced DNA methyltransferase 3 A (DNMT3A) chromatin occupancy and DNA demethylation that promote the expression of gene sets related to the transforming growth factor beta (TGF-β)-dependent microglial homeostasis and the microglial sensome. We find that upon repression of Dnmt3a expression in microglia, those cells maintain anti-tumoral attributes in vitro and in vivo. In a syngeneic immunocompetent glioblastoma mouse model, brain delivery of antisense oligonucleotide targeting Dnmt3a expression led to microglial activation and reduced tumor growth. Taken together, our results reveal the involvement of DNA demethylation in the control of glioma cells-induced microglia activation and indicate that microglial DNMT3A is a potentially therapeutic target to treat brain neoplasms such as glioblastoma that include a microglial component.

DOI: https://doi.org/10.1038/s41418-026-01712-x
Cancer Res. 2026 Mar 16. 86(6): 1345-1346

Spatially Resolved Opto-Omics Uncovers Functional Microglial Subtypes in Brain Metastasis.

Ethan J Vallebuona, Inna Smalley.

The tumor microenvironment plays an important role in brain metastasis. To investigate microglial subtypes in the developing metastatic tumor microenvironment in this issue of Cancer Research, Tsuji and colleagues pioneer a cutting-edge approach for mapping the transcriptional fate of live, spatially identified cells using a method they call "opto-omics." Using a mouse model that enables microglia-specific transgenic expression of a photoconvertible fluorescent protein, the authors profile disease-associated microglia in spatial proximity to disseminated tumor cells (DTC) through intracerebral windows installed in the mouse skull. Microglia that spatially migrate to DTCs are photoconverted, and transcriptional profiling of these microglia reveals an overall enrichment in inflammatory gene programs with five distinct subpopulations corresponding to biological processes such as antigen presentation, type II IFN response, phagocytosis, TGFβ signaling, and tissue repair. This article describes a strategy to modulate the relative abundance of individual microglial subpopulations through pharmacologic perturbation of specific pathways, such as TGFβ, or through genetic ablation of "don't eat me" signals to reprogram protumor microglia. By developing opto-omics and demonstrating its functional integration with single-cell transcriptomics, the authors present a versatile platform for phenotypic profiling that may be applied in numerous areas of research. See related article by Tsuji et al., p. 1414.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5539
Nat Immunol. 2026 Mar 18.

Distinct origins and niches determine the cellular responsiveness of CNS macrophages after repopulation.

Maximilian Fliegauf, Damien Levard, Francesco Cardamone, Maximilian Frosch, Siegmar Kuhn, Roman Sankowski, Martino Provinciali, Anaelle Aurelie Dumas, Adrià Dalmau Gasull, Philipp Aktories, Alexander Oschwald, Marius Schwabenland, Rebekka Scholz, Marc D Beyer, Jonas J Neher, Michael Kollefrath, Dimos Baltas, Wilfried Reichardt, Dominik von Elverfeldt, Denis Vivien, Jovana Cupovic, Nicola Iovino, Marina Rubio, Lukas Amann, Marco Prinz.

Nonparenchymal central nervous system (CNS)-associated macrophages (CAMs) mediate immune responses at brain boundaries. Perivascular and leptomeningeal CAMs are collectively termed subdural CAMs (sdCAMs). Both sdCAMs and juxtaneuronal microglia are derived from embryonic yolk sac precursors, long-living and maintain their populations through self-renewal. Following depletion, microglia autonomously repopulate from single surviving cells. In contrast, the course of sdCAM repopulation remains poorly understood. Here, by combining multilineage fate mapping, multiomic profiling and high-resolution imaging, we demonstrate divergent repopulation dynamics between sdCAMs and microglia. Unlike microglia, sdCAMs do not renew cell-autonomously, but become transiently accessible to CCR2+Ly6C+ monocyte engraftment after niche induction in an integrin-dependent manner. Moreover, replenished monocyte-derived sdCAMs remain transcriptomically, epigenetically and functionally distinct from their embryo-derived counterparts. Finally, we present a protocol enabling selective exchange of sdCAMs, modulating disease response without functionally affecting microglia. These new insights into CNS immune biology suggest new therapeutic avenues for neuroinflammatory and neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41590-026-02457-y
Exp Eye Res. 2026 Jan;pii: S0014-4835(25)00468-3. [Epub ahead of print]262 110695

OGG1 modulates the crosstalk of microglia and Müller cells in degenerative retinas via alleviating inflammatory response and oxidative stress.

Miao Li, Yange Wang, Siyu Li, Yuanmeng Wei, Gang Wang, Enming Du, Zixu Huang, Beibei Zhang, Ye Tao, Zongming Song.

  Oxidative stress and neuroglial-driven inflammation are crucial in the pathogenesis of retinal degeneration (RD). 8-hydroxyguanine DNA glycosylase 1 (OGG1), a key enzyme in repairing oxidative DNA damage via the base excision repair (BER) pathway, also regulates inflammatory responses. Using the sodium iodate (NaIO3)-induced oxidative stress model in C57BL/6J mice, we investigated the temporal dynamics of OGG1 expression and its functional role in RD. To specifically inhibit OGG1 activity, TH5487 - a potent and highly selective OGG1 inhibitor-was administered via intravitreal injection, rapidly and reversibly creating a functional OGG1-deficient state. We observed a significant initial upregulation of OGG1 at the onset of RD, followed by a rapid decline as photoreceptor degeneration progressed. OGG1 deficiency exacerbated DNA oxidative damage and impaired its repair capacity. Immunostaining revealed pronounced neuroglial activation in RD retinas, with microglial activation preceding Müller cell gliosis. Intravitreal delivery of exogenous OGG1 suppressed neuroglial activation, mitigated photoreceptor loss, and partially restored electroretinogram (ERG) responses. These protective effects were reversed by co-administration of OGG1+TH5487. In vitro assays demonstrated that OGG1 alleviates oxidative stress, preserved mitochondrial integrity in microglia, and subsequently modulated the gliotic response of Müller cells. Mechanistically, OGG1 deficiency accelerates RD progression by disrupting oxidative damage repair and amplifying neuroinflammatory cascades. Conversely, OGG1 supplementation coordinates retinal protection through a dual mechanism: directly repairing oxidative DNA lesions and indirectly modulation of the neuroinflammatory microenvironment by suppressing microglia-driven inflammation and Müller cell gliosis. These findings establish OGG1 as a central regulator linking oxidative DNA damage to neuroglial dysfunction in RD. Clinically, targeted OGG1 delivery represents a promising therapeutic strategy for degenerative retinopathies by concurrently addressing oxidative injury and neuroinflammation.

Keywords:  Inflammation; Neuroglia; Oxidative stress; Photoreceptor death

DOI:  https://doi.org/10.1016/j.exer.2025.110695
EMBO Mol Med. 2026 Mar 20.

Blocking microglial reactivity via purinergic receptors prevents subacute cognitive deficits after TIA.

Gemma Llovera, Steffanie Heindl, Daniel P Varga, Nikolett Lenart, Sebastian Kallabis, Vanessa Göb, David Stegner, Raphael Escaig, Leo Nicolai, Nicolai Franzmeier, Felix Meissner, Adam Denes, Arthur Liesz.

  Our research presents a new animal model of transient ischemic attack (TIA) that mimics brief episodes without cell loss, but results in neuronal and behavioral deficits. We identified excessive microglial reactivity, driven by acute ATP release, as a key factor in post-TIA neurological deficits, which were ameliorated by inhibiting the P2Y12 receptor, a microglia-specific purinergic receptor in the brain parenchyma responsible for activity-dependent microglial cell-cell interactions. This finding suggests that modulation of microglial reactivity offers a promising strategy to prevent cognitive impairment in TIA patients, opening avenues for future research in this underexplored area.

Keywords:  ATP; Microglia; Purinergic Receptor; Synapse; TIA

DOI:  https://doi.org/10.1038/s44321-026-00397-6
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2521256123

Microglial fructose metabolism is essential for glioblastoma growth.

Leah K Billingham, Susan L DeLay, Yasmina Eshac, Tzu-Yi Chia, Shashwat Tripathi, Ian E Olson, Kaylee Zilinger, Jay Subbiah, Zhaoquan Wang, Nishanth S Sadagopan, Hinda Najem, Guillaume Cognet, Joshua L Katz, Ruochen Du, Khizar R Nandoliya, Lauren K Boland, Gustavo Ignacio Vázquez-Cervantes, Si Wang, Hanxiao Wan, Allie B Lipshutz, Alina R Murphy, Joseph Duffy, Irina V Balyasnikova, Peng Zhang, Dieter Henrik Heiland, Atique U Ahmed, Catalina Lee-Chang, Amy B Heimberger, Justin S A Perry, Alexander Muir, Navdeep S Chandel, Jason Miska.

  Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors in adults. Its immune microenvironment is dominated by tumor-associated macrophages, including both infiltrating monocytes and brain-resident microglia. While metabolic rewiring of infiltrating myeloid cells has been shown to support tumor progression, the role of microglial metabolism in GBM remains incompletely understood. Here, we demonstrate that microglia uniquely express the fructose transporter GLUT5 and are the only immune cells in the GBM microenvironment capable of metabolizing fructose. Using murine orthotopic glioma and Replication-Competent Avian sarcoma leuko virus Splice acceptor (RCAS)-derived tumor models, we show that global deletion of GLUT5 confers profound resistance to tumor growth. This effect is driven by loss of fructose metabolism in microglia and occurs independently of contributions from peripheral immune compartments. In GLUT5-deficient mice, tumors exhibit increased infiltration and activation of both innate and adaptive immunity, including enhanced antigen presentation, clonal expansion of CD8+ T cells, and increased cytokine production. Depletion of B-cells or CD8+ T cells abrogated survival phenotypes in knockout mice, demonstrating that GLUT5 suppresses adaptive immunity. These findings identify microglial fructose metabolism as a critical regulator of immune suppression in GBM and suggest that targeting this pathway may improve immunotherapeutic responses.

Keywords:  fructose metabolism; glioblastoma; microglia; redox homeostasis

DOI:  https://doi.org/10.1073/pnas.2521256123
Science. 2026 Mar 19. 391(6791): eaee6177

From chronic pain to depression: Neurogenesis-driven microglial remodeling in the hippocampal dentate gyrus.

Ming Ding, Shitong Xiang, Yuqing Zhang, Lei Wei, Yuanfeng Weng, Xueting Zhang, Yiling Ni, Yuwen Zhang, Qianfeng Wang, Ruiqing Hou, Huaihao Du, Ka Kei Chio, Wei Zhang, He Wang, Tianye Jia, Yi Wu, Jianfeng Feng, Trevor W Robbins, Xiao Xiao.

Chronic pain often evolves into depression and anxiety, yet mechanisms linking sensory distress to affective dysfunction remain unclear. Integrating human neuroimaging from the UK Biobank with a rodent model, we uncovered biphasic hippocampal remodeling. Hippocampal volume increased during early pain stages, with paradoxical cognitive improvements, but declined with comorbid depression. In rodents, the dentate gyrus (DG) acted as a hub governing this transition: Lesions of DG prevented affective symptoms. Elevated DG activity was linked to hyperactive newborn neurons and microglial recruitment and remodeling, leading to circuit imbalance. Whereas suppressing newborn neuron activity alleviated emotional pathology at the expense of cognition, microglial modulation selectively restored affective behavior without cognitive cost. These findings reveal microglia-mediated hippocampal remodeling as a key mechanism linking chronic pain to mood disorders.

DOI: https://doi.org/10.1126/science.aee6177
Acta Pharmacol Sin. 2026 Mar 20.

Microglial NLRP3-dependent pyroptosis promotes cognitive dysfunction of diabetic encephalopathy by inhibiting adult hippocampal neurogenesis through the release of IL-1β.

Meng-Yu Hua, Shan Huang, Zi-Yun Zhuang, Xiao-Lin Han, Xiao-Jing Liu, Zhong-Hao Liang, Neng-Jun Lou, Feng-Jie Zheng, Li Lv, Xiang-Hua Zhuang, Shu-Yan Yu, Shi-Hong Chen.

  Diabetic encephalopathy (DE) is a prevalent complication of diabetes which can lead to cognitive dysfunction, without effective therapy currently. In diabetic patients, a reduction in adult hippocampal neurogenesis (AHN) is a heightened risk of cognitive impairment, which may be associated with neuroinflammation caused by microglia. In this study, we established a DE mouse model and conducted in vitro cultures of microglial cells and neural stem cells. Our study demonstrated that the high-glucose associated with DE impairs AHN and induces microglial NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) dependent pyroptosis. Further investigation showed that upregulation of microglial NLRP3 promotes the activation of Gasdermin D (GSDMD), the key pyroptosis effector, and the cleavage of pro-interleukin-1β (pro-IL-1β) by caspase-1, exacerbated pyroptosis and induced release of IL-1β, which might lead to impaired AHN and subsequent cognitive dysfunction. Conversely, downregulation of microglial NLRP3 inhibited caspase-1 activation and pyroptosis, reduced release of IL-1β, improved AHN, and rescued cognitive deficits in DE mouse model. Such findings suggest that targeting microglial NLRP3 inflammasome-mediated pyroptosis may be an important potential therapeutic target for treating DE.

Keywords:  IL-1β; NLRP3 inflammasome; adult hippocampal neurogenesis; cognitive dysfunction; diabetic encephalopathy; pyroptosis

DOI:  https://doi.org/10.1038/s41401-026-01774-0
Anal Chem. 2026 Mar 18.

Fe-Doped Carbon Dots Functionalized Nanoelectrode for In Situ Monitoring of Metabolism-Associated ROS Changes in Single Microglia.

Hong Jiang, Ya-Qin Wang, Xiao-Yang Dong, Dong Zhao, Yuan-Yuan Wei, Zhao-Peng Liu, Ji-Dong Wang.

In metabolic reprogramming, reactive oxygen species (ROS) serve not only as harmful byproducts but also as essential signaling molecules that drive reprogramming processes to establish new metabolic homeostasis. Therefore, the in situ monitoring of ROS changes during metabolic reprogramming is crucial for understanding metabolic changes. Herein, we develop an Fe-doped carbon dots (FeCDs)-functionalized nanoelectrode that exploits the excellent catalytic activity of FeCDs to achieve in situ monitoring of intracellular ROS in single microglia under a neuroinflammatory microenvironment mimicking Alzheimer's disease. Further investigations reveal that cordycepin may target hexokinase II, a key regulatory enzyme in glucose metabolism, thereby inducing metabolic reprogramming in microglia and mitigating the LPS + Aβ-induced elevation in intracellular ROS. This work provides an efficient strategy for in situ monitoring of ROS changes during metabolic reprogramming at the single-cell level, which is vital for advancing disease diagnosis and therapeutic development.

DOI: https://doi.org/10.1021/acs.analchem.5c07646
Mol Ther. 2026 Mar 13. pii: S1525-0016(26)00104-8. [Epub ahead of print]

Microglia-independent rAAV-induced inflammation causes persistent ocular immune dysregulation rescued by S1P receptor modulation.

Philip M Langer, Alison J Clare, Xudong Peng, Katherine L Costello, Suci Cendanawati, Leslie L Wilson, Amy Ward, Oliver H Bell, Colin J Chu, Ying Kai Chan, Andrew D Dick, Kathryn L Pepple, David A Copland.

Inflammation elicited by rAAV vectors continues to present a critical challenge for long-term efficacy and safety of gene therapy in the eye. Preclinical models of gene therapy-associated uveitis (GTAU) show that despite resolution of early acute inflammatory response, persistent subclinical inflammation remains. Here, we employ the GTAU model in Cx3cr1CreER:R26-tdTomato+/- mice to reveal that intravitreal (IVT) rAAV2 administration elicits sustained microglial dysregulation and retention of CD3+ T cells extending to 50 days post-injection (dpi). Deploying pharmacological and genetic approaches, we define the absolute requirement for microglia and T cells to mediate rAAV2-induced inflammation. Targeted depletion confirmed microglia-independent mechanisms initiate GTAU, whilst elimination of lymphocytes prevented both inflammation and microglial activation. Systematic evaluation of therapeutic strategies reveals identified inhibition of T cell recruitment via sphingosine-1-phosphate receptor modulation, but not B cell depletion, as an effective steroid-sparing strategy to prevent both acute and long-term subclinical inflammation. Collectively, our findings challenge the paradigm of microglia-driven ocular inflammation and support the utility of targeted T cell immunomodulation strategies to control GTAU and maintain long-term ocular homeostasis.

DOI: https://doi.org/10.1016/j.ymthe.2026.02.018
Cell Death Discov. 2026 Mar 18.

Myeloid HDAC3 deletion protects against traumatic optic injury.

Rami A Shahror, Carol A Morris, Ashlynn Cunningham, Piyanan Chuesiang, Abdelrahman Y Fouda.

Traumatic optic neuropathy (TON) occurs due to trauma to the optic nerve, resulting in blindness. Current management focuses primarily on supportive care, highlighting an urgent need to identify novel treatment targets. Neuronal expression of the enzyme histone deacetylase 3 (HDAC3) has been previously implicated in retinal ganglion cell (RGC) degeneration after optic nerve crush (ONC), a model of TON. Here we investigated the role of myeloid HDAC3 (i.e., HDAC3 expressed in microglia and macrophages) in RGC loss, axonal degeneration, and efferocytosis, a reparative process by which phagocytic myeloid cells engulf apoptotic cells. ONC injury was performed on myeloid-specific HDAC3 knockout (KO) and floxed control mice. Neurodegeneration and efferocytosis assays were assessed using retina flatmount immunolabeling and confocal imaging. RGC function was evaluated using pattern electroretinography (PERG). Axonal sprouting was quantified by anterograde transport of cholera toxin B injected intravitreally. Myelin debris clearance was assessed in optic nerves in vivo and in vitro using bone-marrow-derived macrophages isolated from myeloid HDAC3 KO and control mice. Myeloid HDAC3 deletion preserved RGC and improved axonal regeneration after ONC, together with improved retinal function assessed by PERG. Furthermore, the deletion of HDAC3 enhanced the phagocytic function of myeloid cells to effectively remove apoptotic cells and myelin debris, both in vivo and in vitro. These protective effects were associated with the deletion of HDAC3 specifically in macrophages, since microglial-only deletion of HDAC3 did not preserve RGC count or function. The enhanced efferocytosis function of HDAC3 KO macrophages was at least partly dependent on increasing the expression of the phagocytic tyrosine kinase receptor, MerTK. The deletion of myeloid HDAC3 enhances efferocytosis, leading to neuroprotection, regeneration, and functional recovery following ONC. Targeting myeloid-HDAC3 presents a novel therapeutic strategy for TON.

DOI: https://doi.org/10.1038/s41420-026-03030-0
Redox Biol. 2026 Mar 12. pii: S2213-2317(26)00125-4. [Epub ahead of print]92 104127

SLC22A3 deficiency leads to cognitive impairment through the cardio-neuroinflammatory axis mediated HA/H1R/NLRP3 pathway in heart failure mice.

Zhitian Wang, Lv Zhou, Na Zhao, Tianxiao Li, Fan Geng, Jingting Kong, Yahao Zhang, Zhijun Zhang, Qing-Guo Ren.

  Heart failure (HF) affects over 64 million individuals worldwide and is strongly associated with cognitive impairment (CI), yet the underlying mechanisms remain poorly understood. Here, we identify solute carrier family 22 member 3 (SLC22A3) might be a candidate gene for HF-induced CI through Mendelian randomization and bioinformatics analysis. To investigate its functional role in vivo, we established a mouse model of HF after myocardial infarction (MI). Cognitive performance was evaluated using the Morris water maze. Expression of SLC22A3, blood-brain barrier (BBB) integrity, and neuroinflammatory signalling were examined via immunofluorescence and Western blotting. The involvement of the HA/H1R/NLRP3 signalling pathway was further evaluated using cardiac-specific SLC22A3 overexpression mice, hippocampal-specific H1R knockdown mice, NLRP3 knockout mice, and BV2 cell assays. Consistent with the findings in HF patients, cardiac SLC22A3 expression was dramatically downregulated in HF mice, accompanied by an increase in peripheral histamine (HA) levels, while HA levels in the mouse brain were also significantly raised. Using cardiac-specific SLC22A3 overexpression in HF mice, we demonstrated that restoring SLC22A3 reduced HA accumulation and improved cognitive performance. Mechanistically, HA breached the compromised BBB in HF mice, activating hippocampal microglia H1 receptor (H1R) and the NLRP3 inflammasome. In BV2 cells, HA stimulation elevated NLRP3 expression in a dose-dependent manner, an effect blocked by H1R antagonist. Knockdown of H1R or NLRP3 in the hippocampus attenuated neuroinflammation and rescued HF-induced CI. Our findings unveil a novel cardio-neuroinflammatory axis driven by SLC22A3 deficiency, highlighting HA/H1R/NLRP3 pathway as a therapeutic target for HF-induced CI.

Keywords:  Cardio-neuroinflammatory axis; Cognitive impairment; Heart failure; Histamine; NLRP3 inflammasome; SLC22A3

DOI:  https://doi.org/10.1016/j.redox.2026.104127
Adv Healthc Mater. 2026 Mar 15. e71049

A BBB-Penetrating Fullerene Mediates Recovery from Intracerebral Hemorrhage via Dually Promoting Hematoma Clearance and Neuroprotection.

Yuyang Peng, Lei Liu, Yong Huang, Jing Ma, Hedong Qi, Jingchao Liu, Huiqiang Lu, Xue Li, Chunru Wang.

  Current pharmacologic intervention for intracerebral hemorrhage (ICH) is severely limited by insufficient blood-brain barrier (BBB) penetration and complicated secondary injury mechanisms. To address this, we developed a multi-pronged therapeutic strategy for ICH utilizing a BBB-penetrating tetra malonic acid derivative of C70 fullerene (TMF), which dually accelerates hematoma clearance and mitigates perihematomal damage. Following intravenous administration, TMF crossed the BBB via clathrin-mediated endocytosis in cerebral microvascular endothelial cells and accumulated in brain tissue. It promoted hematoma resolution and improved motor deficits in both zebrafish and mouse ICH models. Mechanistically, TMF reduced microglial oxidative stress, leading to its polarization toward the M2 phenotype. This shift enhanced phagosome signaling and degradation functions while attenuating neuroinflammation. Additionally, TMF exhibited direct neuroprotection by resisting oxidative stress, iron toxicity, and apoptosis, collectively constituting its pleiotropic therapeutic mechanisms. In summary, this study overcomes the major challenges in ICH therapeutics, offering a promising candidate for clinical intervention.

Keywords:  blood‐brain barrier penetration; fullerene; hematoma clearance; intracerebral hemorrhage; microglial polarization; neuroprotection

DOI:  https://doi.org/10.1002/adhm.71049