HCAR2 / ImmunoACT - LARVOL DELTA

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

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)... IL-10 and MR-proADM were significant penumbra markers, reflecting anti-inflammatory and vasodilatory mechanisms. 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

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

Structural insights into the activation mechanism of the human metabolite receptor HCAR1. (PubMed, Sci Signal) - "Structural comparisons with HCAR2 identified critical residues that restrict the size of the binding pocket of HCAR1 and influence ligand selectivity. Self-activation of HCAR1 is driven by conformational rearrangements within extracellular loop 2, with Phe168ECL2 playing a pivotal role as the key agonist. Together, these results clarify the mechanisms underlying HCAR1 activation, self-activation, and ligand selectivity, providing a structural framework for the design of high-affinity, selective agonists and inverse agonists with minimized off-target effects."

Journal • Inflammation • MAGEE1

Monomethyl fumarate confers cardioprotection after myocardial infarction via HCAR2-dependent activation of PI3K/Akt signaling. (PubMed, Cell Death Discov) - "Pharmacological inhibition of Gi-coupled signaling with pertussis toxin or siRNA-mediated knockdown of HCAR2 abolished MMF's cytoprotective effects and blunted MMF-induced Akt phosphorylation, and PI3K/Akt pathway inhibition eliminated MMF's anti-apoptotic benefits in vitro. Collectively, these findings demonstrate that MMF markedly reduces ischemic cardiomyocyte injury via an HCAR2-dependent mechanism involving activation of the pro-survival PI3K/Akt pathway, establishing a novel cardioprotective role for MMF and supporting its translational potential as a therapeutic strategy to mitigate acute MI injury."

IO biomarker • Journal • Cardiovascular • CNS Disorders • Coronary Artery Disease • Dermatology • Heart Failure • Immunology • Infectious Disease • Multiple Sclerosis • Myocardial Infarction • Psoriasis • Respiratory Diseases • BAX • BCL2 • CASP3

Basic Science and Pathogenesis. (PubMed, Alzheimers Dement) - "Our findings suggest that alterations in hippocampal HCAR2 expression may play a role in tau pathology. Niacin treatment improved motor coordination but did not affect the clasping reflex. In addition, niacin improved expression patterns of structural synaptic proteins. These results indicate that HCAR2 activation may help reduce disease severity. However, further studies are needed to clarify the underlying mechanisms. Overall, this research highlights a novel role for HCAR2 in tauopathies and supports the potential repurposing of existing niacin formulations as a therapeutic approach for Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • CLSPN,

HCAR2 Orchestrates an Immunosuppressive Niche and Determines Checkpoint Inhibitor Responsiveness in Esophageal Squamous Cell Carcinoma. (PubMed, Biol Proced Online) - No abstract available

Checkpoint inhibition • Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma

Rebalancing the inflammatory niche in allergic rhinitis ". (PubMed, Clin Chim Acta) - "In this review we focus on defined signaling axes by which Traditional Chinese Medicine (TCM) can influence that network: (1) microbially produced short-chain fatty acids (SCFAs), particularly butyrate, suppress ILC2 proliferation and type-2 cytokine output primarily via HDAC inhibition that downregulates the lineage transcription factor GATA3; receptor-dependent effects via the SCFA sensors FFAR3 (GPR41), FFAR2 (GPR43), and GPR109A (HCAR2) also occur in some cell types and tissues, and can engage β-arrestin/ERK or AMPK-linked pathways depending on cell context...Together these actions provide testable, mechanism-based routes to suppress ILC2 activation and restore mucosal homeostasis in AR. We explicitly link TCM-driven microbiome/metabolome changes to canonical molecular mediators (HDAC, GPR41/43, FXR/TGR5, AhR, TSLP/IL-33, HMGB1) to facilitate mechanistic trial design that measures taxa → metabolite → receptor/epithelial → ILC2 causal chains."

Journal • Review • Allergic Rhinitis • Immunology • Inflammation • GATA3 • HMGB1 • IL13 • IL33 • IL5 • TSLP

Structures of G-protein coupled receptor HCAR3 in complex with selective agonists reveal the basis for ligand recognition and selectivity. (PubMed, PLoS Biol) - "Moreover, combined with cAMP assay in HEK-293 cells, we have elucidated that the ligand selectivity between HCAR3 and HCAR2 depended on π-π interaction with F1073.32 (L1073.32 in HCAR2) and ligand-binding pocket size difference, facilitated by key residues difference V/L832.60, Y/N862.63, and S/W9123.48. Collectively, these structural insights lay the groundwork for developing HCAR3-specific drugs, potentially avoiding HCAR2-induced adverse effects."

Journal • Dyslipidemia • Metabolic Disorders

HCAR score as a prognostic biomarker of survival in locally advanced nasopharyngeal carcinoma treated with concurrent chemoradiotherapy. (PubMed, Biomol Biomed) - "Receiver operating characteristic curve analysis determined pretreatment hemoglobin (Hb) and C-reactive protein-to-albumin ratio (CAR) cut-offs of 11.0 g/dL and 3.0, respectively, which were utilized to create a three-tiered HCAR score: HCAR-0 (Hb ≥11.0 g/dL and CAR <3.0), HCAR-1 (Hb ≥11.0 g/dL and CAR ≥3.0 or Hb <11.0 g/dL and CAR <3.0), and HCAR-2 (Hb <11.0 g/dL and CAR ≥3.0)...Corresponding 10-year PFS rates were 50.2%, 34.4%, and 5.0%, while 10-year OS rates were 68.3%, 41.6%, and 11.1%. Multivariate analysis revealed that the HCAR score remained an independent predictor of both PFS and OS, alongside T and N stage. The HCAR score shows promising prognostic utility for predicting OS and PFS in LANPC; however, performance estimates may be overly optimistic due to the lack of internal validation."

Biomarker • Journal • Head and Neck Cancer • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • CRP