C-X-C chemokine receptor 4

Overview

C-X-C chemokine receptor 4 (CXCR4) is a chemokine receptor and G protein-coupled receptor (GPCR) that binds the chemokine C-X-C motif chemokine ligand 12 (CXCL12), also known as stromal cell-derived factor 1 (SDF-1α). It is widely recognized as a key mediator of cell migration, tissue homing, immune cell trafficking, and tumor-stromal communication. Through CXCL12-dependent signaling, CXCR4 can activate downstream pathways including JAK2/STAT3 signaling, influencing proliferation, survival, inflammatory responses, and remodeling processes in both normal physiology and disease.

In biomedical research, CXCR4 is an important therapeutic target because it is implicated in cancer progression, fibrosis, pulmonary vascular disease, and inflammatory pathology. It is also used as a molecular target for imaging and drug delivery strategies, including radiolabeled Peptides and antagonists such as plerixafor (AMD3100). Recent studies continue to explore CXCR4 as both a mechanistic driver of disease and a targetable receptor for intervention.

Focus of Latest Publications

Recent publications have focused heavily on CXCR4 as a therapeutic and imaging target in inflammatory disease, hematologic malignancy, and receptor pharmacology. In cardiovascular research, a series of novel 68Ga-labeled small-molecule CXCR4 radiotracers was developed for PET imaging of atherosclerotic plaque inflammation. Among the candidates, [68Ga]Ga-SDNUM11 showed the most favorable combination of hydrophilicity, rapid blood clearance, stability, and binding affinity, and demonstrated focal uptake in a rat carotid atherosclerosis model that colocalized with CXCR4-positive plaques. These findings support CXCR4-targeted PET as a potential approach for assessing plaque inflammation and cardiovascular risk.

Several studies examined CXCR4 in leukemia biology and treatment. In acute myeloid leukemia, a lipid nanoparticle system was engineered to deliver AML1-ETO siRNA together with the CXCR4 antagonistic peptide E5, simultaneously suppressing the fusion oncogene and inhibiting CXCR4 activation. In refractory AML models, this dual strategy promoted multilineage differentiation, enhanced apoptotic responses to homoharringtonine, and prolonged survival. Another study identified METTL1 as an upstream regulator of leukemia stem cell homeostasis through a tRNAPheGAA/HCK/CXCR4 axis; pharmacologic METTL1 inhibition reduced CXCR4 signaling, impaired leukemia stem cell self-renewal and bone marrow homing, and delayed leukemogenesis in multiple AML models.

CXCR4 has also been investigated in inflammatory lung disease and vascular pathology. In advanced silicosis, multi-omics analysis revealed a novel Cxcr4+ alveolar macrophage subpopulation, and prior work cited in the abstract showed that inhibition of Cxcr4 with AMD3100 attenuated pulmonary fibrosis. In abdominal aortic aneurysm, CXCR4 emerged as one of four genes in a machine-learning-derived diagnostic signature associated with NETs-related inflammation, with the model showing strong diagnostic performance and CXCR4 contributing prominently to discrimination between disease groups.

Additional publications addressed CXCR4 receptor biology and translational radiopharmaceutical development. Computational studies mapped the activation mechanism of CXCR4, identifying distinct transition states and key conformational changes, and used these insights to design HL82624, a small-molecule CXCR4 agonist that bound the receptor and induced cell migration. Separately, an optimized CXCR4-targeting theranostic pair, [68Ga]Ga/[177Lu]Lu-BL34, was developed from a cyclic peptide scaffold; the agents showed strong CXCR4 binding, high tumor uptake in a mantle cell lymphoma model, favorable renal clearance, and dose-dependent therapeutic benefit with the 177Lu-labeled compound.

Key Publications

• NEWJun Synthesis and Preclinical Evaluation of Structurally Optimized 68Ga-Labeled CXCR4 Radiotracers for PET Imaging of Atherosclerotic Plaque Inflammation. (Journal of medicinal chemistry, 2026, PMID 42258221): "...with CXCR4 playing a critical role in plaque inflammation and disease progression."
• Jun Targeting the METTL1/m7G axis as a therapeutic strategy in myeloid leukemia. (Blood, 2026, PMID 42247311): "Decreased HCK expression disrupts CXCR4 signaling, impairing LSC self-renewal and BM homing."
• Jun CXCR4 antagonistic lipid nanoparticles loading siRNA combat refractory AML through AML1-ETO depletion and homoharringtonine sensitization. (Materials today. Bio, 2026, PMID 42211065): "The disease-causing fusion protein AML1-ETO (also known as RUNX1-ETO or RUNX1-RUNX1T1) and the chemokine (C-X-C motif) receptor 4 (CXCR4) have been recognized as crucial effectors."
• Jun Multi-omics reveals a novel Cxcr4+ subpopulation of alveolar macrophages and therapeutic effect of AMD3100 in mice with advanced silicosis. (Clinical and translational medicine, 2026, PMID 42204838): "Our previous studies demonstrated that inhibition of Cxcr4 with Plerixafor (AMD3100) markedly attenuates pulmonary fibrosis."
• May Machine learning identifies a NETs-related four-gene diagnostic signature for abdominal aortic aneurysm. (Medicine, 2026, PMID 42175497): "A robust 4-gene diagnostic signature comprising CXCR4, GZMB, ITGA6, and CD47 was identified."
• May Computational Insights into the Activation Mechanism of CXCR4: Implications for the Design of Small Molecule Agonists. (Journal of the American Chemical Society, 2026, PMID 42126261): "The chemokine receptor CXCR4, a GPCR, plays multifaceted roles in both normal physiological and pathological processes."
• May Development of an Optimized CXCR4-Targeting Theranostic Pair. (Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2026, PMID 41611474): "We developed a new C-X-C chemokine receptor 4 (CXCR4)-targeting radiolabeled peptide, [68Ga]Ga/[177Lu]Lu-BL34, using a novel and potent cyclic peptide based on structure-activity relationship studies of LY2510924."