HCAR2 / ImmunoACT - LARVOL DELTA

Chronic Ileitis Ameliorates Hyperglycemia via a 3-HB/NKX6.1 Axis in Mice. (PubMed, Mol Cell Endocrinol) - "Furthermore, exogenous administration of 3-HB recapitulated these protective effects in diabetic mice. This study identifies a novel gut-islet axis where microbiota-derived 3-HB preserves β-cell functional identity via HCAR2 dependent regulation of NKX6.1, offering a potential therapeutic strategy for type 2 diabetes."

Journal • Preclinical • Diabetes • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Metabolic Disorders • Type 2 Diabetes Mellitus • IL10

Hematopoietic HCAR2 attenuates atherosclerosis by enhancing efferocytosis via AMPK/ABCA1 signaling. (PubMed, Int Immunopharmacol) - "HCAR2 activation is associated with enhanced macrophage efferocytosis and reduced atherosclerotic plaque burden, correlating with Ca2+/cAMP-mediated AMPK/ABCA1 pathway engagement. These findings suggest a potential mechanistic link between HCAR2 and efferocytosis, but the causal relationship remains to be established. Notably, the in vivo role of the ABCA1 pathway was not validated in this study."

Journal • Atherosclerosis • Bone Marrow Transplantation • Cardiovascular • Inflammation • Metabolic Disorders • Transplantation • ABCA1 • APOE • CAMKK2 • STK11

A Niacin-α-Lipoic Acid Hybrid Ameliorates Alzheimer's Disease Pathology in Mouse Models. (PubMed, ACS Pharmacol Transl Sci) - "Niacin and α-lipoic acid have been reported to exhibit therapeutic potential in AD through distinct biological activities, including GPR109A/HCAR2 agonism and antioxidant effects, respectively...Additionally, N2L increased the relative abundance of beneficial gut microbial taxa, including Lactobacillus, Bifidobacterium, and Faecalibaculum, suggesting a potential modulation of the microbiota-gut-brain axis. These findings demonstrate that N2L exerts multifaceted protective effects against AD-related pathological alterations and support its further development as a potential therapeutic candidate for AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders

Research on the role of gut microbiota metabolites in autism by multi-omics and network pharmacology. (PubMed, Front Microbiol) - "The findings demonstrated that five characteristic targets: CXCR3, HCAR2, HTR1A, IL-6 and NFKB1 modulated by the gut microbiota and gut microbiota's metabolites were significantly associated with ASD...By integrating network pharmacology, transcriptomic re-analysis, fecal metabolomics and 16S rRNA sequencing, this study identifies candidate microbe-metabolite-target associations related to ASD-like phenotypes. These results provide testable hypotheses for future mechanistic studies of gut-brain communication in ASD."

Journal • Autism Spectrum Disorder • CNS Disorders • Gastrointestinal Disorder • Genetic Disorders • Metabolic Disorders • CXCR3 • IL6

Targeting chaperone-mediated autophagy by nutritional interventions mitigates age-related cardiac fibrosis and diastolic dysfunction. (PubMed, Autophagy) - "Furthermore, we show that Lycium barbarum polysaccharide (LBP) rejuvenates hepatic ketogenesis and mimics the benefits of BHB. Our findings establish a BHB-HCAR2-CMA-SHMT2 regulatory axis as a critical mechanism driving aging-related cardiac fibrosis and highlight nutritional strategies that target CMA as promising therapies against cardiac aging."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • HSPA8 • SHMT2

Oxidized Starch-Chitosan-Mg2+ Gel Enhances Colonic Mg2+ Absorption in Deficient Mice with Associated SCFAs and Transporter Modulation. (PubMed, J Agric Food Chem) - "Mechanistically, resistant polysaccharides were associated with upregulation of SCFAs receptors (FFAR2/FFAR3/HCAR2) and Mg2+ transporters (TRPM6/TRPM7/CNNM4), with immunofluorescence indicating TRPM7 upregulation. This work provides proof-of-concept evidence for a paradigm shift from passive supplementation to active regulation via SCFAs-associated transporter modulation."

Journal • Preclinical • TRPM7

Shared Genomic Architecture Between Schizophrenia and Multiple Sclerosis Identifies an Un-Drugged HCAR1 Neuroimmune Checkpoint. (PubMed, bioRxiv) - "While front-line therapeutics, such as Dimethyl Fumarate, achieve clinical efficacy by agonizing the HCAR2 immune cooling switch, the tandemly duplicated HCAR1 lactate sensor has remained entirely unexplored...This enhancer failure renders activated macrophages physically "lactate blind"-unable to sense their own glycolytic exhaust to engage the cAMP-suppressing negative feedback loop required to halt immune proliferation. By bridging psychiatric genetics and neuroimmunology, this study reframes the HCAR tandem array as a master neuroimmune bifurcation point and introduces the un-drugged HCAR1 lactate brake as a critical therapeutic checkpoint for arresting demyelinating disease."

Journal • CNS Disorders • Crohn's disease • Dermatology • Gastroenterology • Immunology • Inflammatory Arthritis • Inflammatory Bowel Disease • Lupus • Multiple Sclerosis • Musculoskeletal Diseases • Orthopedics • Psoriasis • Psychiatry • Rheumatoid Arthritis • Rheumatology • Schizophrenia • MAGEE1

State-Dependent Transcriptomic Collapse of the Brain's Lactate and Ketone Thermodynamic Sensors in Schizophrenia. (PubMed, bioRxiv) - "By integrating high-resolution topological mapping of SCZ GWAS summary statistics, 3D chromatin conformation (Hi-C), and multi-tissue transcriptomics, we identify massive, non-coding structural variances flanking the HCAR2/HCAR1 tandem locus-the brain's master thermodynamic governor...This dual-flank enhancer failure elegantly provides a definitive genomic etiology for historical SCZ biomarkers, physically explaining both chronic cerebrospinal fluid lactate pooling and the infamous "absent niacin flush." Furthermore, peripheral eQTL mapping reveals profound antagonistic pleiotropy, characterized by a hyper-activation of the HCAR1 lactate shuttle in the testis, explaining the evolutionary conservation of this metabolically catastrophic architecture. Ultimately, we reframe Schizophrenia not as an intrinsic neurological defect, but as an evolutionary "fuel mismatch." The high-performance cognitive architecture of the hominid brain, evolved for..."

Journal • CNS Disorders • Musculoskeletal Diseases • Orthopedics • Psychiatry • Schizophrenia • HCAR1 • MAGEE1

Circadian disruption exacerbates crohn's disease by promoting macrophage panoptosis and impairing microbiota-dependent ketogenesis (IDDF 2026) - "Mechanistically, BHB inhibited macrophage PANoptosis by suppressing JAK/STAT signaling via the HCAR2-cAMP axis...Conclusions Circadian disruption exacerbates CD by impairing the gut microbiota-ketone axis, which in turn promotes macrophage PANoptosis and sustains intestinal inflammation. Targeting this axis may represent a novel therapeutic strategy for managing circadian-related disease progression (IDDF2026-ABS-0519 Figure 2).Download figure Open in new tab Download powerpoint Abstract IDDF2026-ABS-0519 Figure 1 Download figure Open in new tab Download powerpoint Abstract IDDF2026-ABS-0519 Figure 2"

Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Sleep Disorder • HMGCS2

Metabolic Gating and the Evolution of Human Cognitive Plasticity: A Comparative Genomic Analysis. (PubMed, bioRxiv) - "Furthermore, we characterize the PDHB and HCAR2 loci as critical metabolic governors against thermal overload and identify structural variance in HDAC2 as the epigenetic clamp linking ancestral fuel availability (β-hydroxybutyrate) directly to the transcriptional control of this plasticity network. We conclude that psychiatric pathology is an emergent property of a fuel-mismatch, wherein a high-performance cognitive architecture is sustained by a carbohydrate-heavy diet, leading to systemic thermodynamic failure. This framework provides a unified, mechanistic explanation for the spectrum between extreme cognitive innovation and pathological collapse."

Journal • CNS Disorders • Psychiatry • Schizophrenia • BDNF • FOXP2 • GRIN2A • HDAC2

Protective Role Of The Niacin Receptor HCAR2 In Tau Pathology (AAIC 2026) - No abstract available

Context-Dependent Short-Chain Fatty Acids in Inflammatory Skin Diseases: Immunometabolic Mechanisms, Evidence Boundaries, and Translational Perspectives. (PubMed, Pharmacol Res) - "SCFAs act through free fatty acid receptors(FFARs), hydroxycarboxylic acid receptor 2(HCAR2), histone deacetylase inhibition(HDAC) and metabolic-substrate effects, but their outcomes depend on species, source, dose, tissue bioavailability, pH, receptor expression, target-cell identity and disease stage...We further evaluate dietary, prebiotic/probiotic, topical, fecal microbiota transplantation, engineered probiotic, prodrug and delivery-based strategies, distinguishing SCFA-specific causality from broader microbiome remodeling. A context-resolved framework is needed to translate SCFA biology into rational immunometabolic interventions for ISDs."

IO biomarker • Journal • Review • Acne Vulgaris • Atopic Dermatitis • Chronic Spontaneous Urticaria • Contact Dermatitis • Dermatitis • Dermatology • Gastrointestinal Disorder • Hidradenitis Suppurativa • Immunology • Inflammation • Psoriasis • Rosacea • Transplantation • Urticaria

Evolutionary history and functional divergence of hydroxycarboxylic acid receptors in primates. (PubMed, Genome Biol Evol) - "Gene expression analyses further show that major divergence in tissue expression occurred early, following the duplication that generated HCAR1 and the HCAR2/3 lineage, while HCAR2 and HCAR3 retain largely overlapping expression profiles. Together, Our results suggest that HCAR3 receptors may have evolved repeatedly in apes, potentially contributing to refined lipid-sensing."

Journal • Metabolic Disorders • MAGEE1

β-hydroxybutyrate potentiates anti-tumor immunity by modulating cytotoxic CD8+ T cell responses. (PubMed, Cancer Immunol Immunother) - "Knockdown of either Tcf7 or Hcar2 in CD8+ T cells abolishes the promoting effect of βOHB on CD8+ T function. Our findings elucidate a metabolite-immune axis that directly regulates the functional state of tumor-infiltrating CD8⁺ T cells and provide experimental evidence linking ketone metabolism to anti-tumor immune regulation."

Journal • Oncology • CD8 • TCF7

Comparative computational analysis of the hypolipidaemic potential of Cordyceps militaris and Ophiocordyceps sinensis, with in vivo validation of cordycepin. (PubMed, Fitoterapia) - "Molecular dynamics simulations showed relatively stable behaviour for the GRIK5-cordycepin and HCAR2-nicotinic acid complexes, whereas ERBB2-cerevisterol exhibited larger conformational fluctuation. Collectively, these findings provide comparative computational insights into the hypolipidaemic potential of C. militaris and O. sinensis, while supporting cordycepin as a bioactive constituent of C. militaris associated with transcriptional changes related to AMPK/SREBP-1c signalling. The predicted regulatory features of O. sinensis still require direct experimental validation."

Journal • Preclinical • Dyslipidemia • Inflammation • Metabolic Disorders • HER-2 • HIF1A

Niacin promotes motor function recovery after spinal cord injury via Hcar2-dependent microglia immunometabolic regulation. (PubMed, Clin Transl Med) - "Hcar2 is identified as a conserved, injury-induced metabolic checkpoint specifically enriched in microglia following spinal cord injury. Hcar2 activation reprogrammes microglial metabolism from glycolysis to oxidative phosphorylation to drive reparative anti-inflammatory polarization. Pharmacological targeting of Hcar2 with niacin resolves neuroinflammation and promotes functional motor recovery in an Hcar2-dependent manner."

Journal • CNS Disorders • Inflammation • Metabolic Disorders • Orthopedics • IL1B • IL6

Multi-omics profiling of gut microbiota and host transcriptome identifies diagnostic signatures and mechanistic links in moyamoya disease. (PubMed, BMC Microbiol) - No abstract available

Journal • Vascular Neurology

HCA2 Receptors in Lymphocytes and Keratinocytes Affect Murine Contact Allergic Inflammation. (PubMed, Exp Dermatol) - "We examined contact allergic immune responses to the obligate contact sensitiser DNFB in Hcar2-/- and wild-type C57BL/6 mice...Our data indicate that the dominant anti-inflammatory effect of HCA2 signalling during the elicitation phase resides in radio-resistant, skin-resident cells, whereas effects on lymphocyte activation are likely to be modulatory. The precise contribution of distinct skin-resident cell populations and the role of endogenous ligands driving HCA2 signalling in this context remain unresolved."

Journal • Preclinical • Allergy • Bullous Pemphigoid • Contact Dermatitis • Dermatology • Dermatopathology • Immunology • Inflammation • Psoriasis • CCL8 • IFNG

Biofluid Markers of Ischemic Penumbra in Stroke: A Systematic Review and Pathway Analysis (AAN 2026) - "Protein–protein network analysis showed IL-1β with highest connectivity (9 interactions), followed by IL-10 (5) and HDAC1/HCAR2 (4)...Markers of leukocyte migration and platelet activation (IL-1β, PF4) were negatively associated. Findings support circulating biomarkers as complementary or alternative tools to imaging for identifying salvageable brain tissue in AIS."

Review • Cardiovascular • Ischemic stroke • AURKA • HDAC1 • IL10 • IL12A • IL1B • NUP98

A fast way to lose antibodies. (PubMed, Immunity) - "In this issue of Immunity, Zhu et al. reveal that fasting-induced β-hydroxybutyrate destabilizes bone marrow plasma cell niches through HCAR2 signaling, accelerating the loss of long-lived plasma cells and humoral immunity."

Journal

HCAR2 activation limits tumor growth by the activation of p53 signaling in breast cancer (AACR 2025) - "Therefore, HCAR2 activation should have a high clinical translational potential for the prevention and treatment of BC by rejuvenating WTp53 and destabilizing p53α in BC cells. Overall, our study provides preclinical evidence to show the functional implication of ketogenic signaling in the regulation of p53 and its relevance to BC prevention and treatment."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC37 • HSP90AA1 • SIRT1

Hydroxycarboxylic acid receptor 2 (GPR109A) and retinopathies: pathways and prospects. (PubMed, Front Med (Lausanne)) - "GPR109A, also known as the hydroxycarboxylic acid receptor 2 (HCAR2), is a G protein-coupled receptor with emerging significance in ocular health...While preclinical data are compelling, further studies are needed to optimize delivery methods, validate efficacy in clinical settings, and overcome translational challenges. Overall, GPR109A represents a promising frontier in the development of preventive therapies for vision-threatening retinal disorders, extending well beyond diabetic retinopathy to conditions such as HR and ROP."

Journal • Review • Diabetic Retinopathy • Inflammation • Ophthalmology • Retinal Disorders • Retinopathy of Prematurity

Niacin Mitigates Cyclophosphamide-Induced Immunosuppression by Maintaining Intestinal Homeostasis and Regulating the HCAR2/NLRP3 and PTGS2/PGE2 Signaling Pathways. (PubMed, Nutrients) - "Further experimental findings showed that niacin markedly decreased the protein expression of PTGS2 and the levels of its downstream mediators PGE2, E-prostanoid receptor type 2 (EP2) and (E-prostanoid receptor type 4 (EP4) in the ileal tissue of mice treated with CTX. In conclusion, niacin supplementation alleviated CTX-induced immunosuppression by maintaining intestinal homeostasis and regulating the intestinal HCAR2/NLRP3 and PTGS2/PGE2/EP2-EP4 pathways."

Journal • Immunology • NLRP3 • PACERR • PTGS2

Fasting impairs humoral immunological memory by β-hydroxybutyrate-mediated depletion of plasma cells. (PubMed, Immunity) - "Activation of the HCAR2-Gαi-adenylate cyclase-cAMP axis by β-hydroxybutyrate downregulated CXCR4, leading plasma cells to exit their bone marrow niche and undergo apoptosis in the periphery. These findings reveal that fasting-induced metabolic signals regulate humoral immunity duration and suggest that diet and lifestyle could influence vaccine effectiveness."

Journal • Infectious Disease • CXCR4

A Machine Learning-Guided Approach for Identifying Potential HCAR1 Antagonists in Lactate-Driven Cancers. (PubMed, ACS Omega) - "An SVM model was trained on 144 ligands (66 agonists, 78 antagonists), listed in the IUPHAR/BPS Guide to Pharmacology, from 12 structurally related Class A GPCRs (HCAR1, HCAR2, HCAR3, OXER1, GPR35, SUCNR1, P2Y2, MCHR1, OPRD1, AGTR1, ADORA2A, and ADRA1A)...Based on ΔAffinity, off-target scores, and prediction confidence, Ketanserin, Cryptopyranmoscatone A1 diacetate, and Cefuroxime emerged as reference ligands with promising antagonistic potential, two of which are FDA-approved drugs...Overall, this work presents a proof-of-concept framework that integrates conformational docking, machine learning, and substructure interpretation to elucidate the chemical and structural determinants of HCAR1 antagonism. The findings provide fragment-level insights that may guide future bioisosteric and fragment-based design of selective antagonists for lactate-driven tumors."

Journal • Oncology • ADORA2A • MAGEE1 • SUCNR1