Backgroud: The E3 ubiquitin ligase casitas B lymphoma-b (Cbl-b) is pivotal in modulating immune responses by attenuating T-cell activation and cytokine production. Inhibiting Cbl-b presents a potential therapeutic strategy in immuno-oncology by enhancing immune activity. Methods: A rapid Homogeneous Time-Resolved Fluorescence (HTRF) assay was employed to evaluate the inhibitory efficacy of NX-1607 on Cbl-b. The effects of NX-1607 on T cell activation, cytokine production, and proliferation were characterized invitro using primary T cells and Jurkat T cells. A drug combination screening was performed utilizing the CD69 marker via flow cytometry to dentify signaling pathways involved in T cell activation by NX-1607. CRISPR/Cas9 technology was used to knock out PLCG1 and MAPK3/1 in Jurkat T cells, followed by the detection of p-PLCγ1 and p-ERK1/2 though Western blotting. The antitumor efficacy of NX-1607 was assessed in a murine model of A20 B-cell lymphoma using BALB/c mice, with subsequent flow cytometry analysis conducted to examine the phenotype of tumor-infiltrating lymphocytes (TILs). Results: Our data show that NX-1607 effectively inhibits Cbl-b activity at low nanomolar levels, boosting PLCγ1 and HCSL1 phosphorylation, activating MAPK/ERK signaling, and elevating CD69 expression. Inhibiting PLCγ1 and ERK1/2 significantly reduces NX-1607's effect on T-cell activation. Oral administration of NX-1607 notably decreases tumor growth in the A20 B-cell lymphoma model, with immunophenotyping analyses of tumor-infiltrating lymphocytes revealing increased CD3+, CD4+, and CD8+ T cells in treated tumors. Furthermore, our results demonstrate that treatment with NX-1607 results in increased levels of phosphorylated PLCγ1 and ERK1/2 in circulating T cells. Conclusion: Taken together, these findings imply that the inhibition of Cbl-b by NX-1607 may enhance the activation of the MAPK/ERK signaling pathway, thereby sustaining T-cell activation. This provides compelling evidence for the molecular mechanism of NX-1607, underscoring the pivotal role of Cbl-b in controlling signal strength in T-cell activation after T-cell receptor (TCR) engagement.
© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

The function of islet macrophages is poorly understood. They promote glucose-stimulated insulin secretion (GSIS) in lean mice, however, the underlying mechanism has remained unclear. We show that activation of the free fatty acid receptor FFAR4 on islet macrophages leads to interleukin-6 (IL-6) release and that IL-6 promotes β-cell function. This mechanism is required for GSIS in lean male mice, but does not function anymore in islets from people with obesity and obese type 2 diabetic male mice. In islets from obese mice, FFAR4 downstream signaling in macrophages is strongly reduced, resulting in impaired FFAR4-mediated IL-6 release. However, IL-6 treatment can still improve GSIS in islets from people with obesity and obese type 2 diabetic mice. These data show that a defect in FFAR4-mediated macrophage activation contributes to reduced GSIS in type 2 diabetes and suggest that reactivating islet macrophage FFAR4 and promoting or mimicking IL-6 release from islet macrophages improves GSIS in type 2 diabetes.
© 2025. The Author(s).

Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon (RAP). Despite its therapeutic effects, the surgical risk and unclear mechanism hamper the clinical application. Numerous evidences support macrophages as the key immune cells during bone remodeling. Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1CreERT2; R26GFP lineage tracing system. Fluorescence staining, flow cytometry analysis, and western blot determined the significantly enhanced expression of binding immunoglobulin protein (BiP) and emphasized the activation of sensor activating transcription factor 6 (ATF6) in macrophages. Then, we verified that macrophage specific ATF6 deletion (ATF6f/f; CX3CR1CreERT2 mice) decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy. In contrast, macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement. In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6. At the mechanism level, RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfα promotor and augmenting its transcription. Additionally, molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element (ERSE). Taken together, ATF6 may aggravate orthodontic bone remodeling by promoting Tnfα transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.
© 2025. The Author(s).

Intervertebral disc degeneration (IDD) is a degenerative spinal condition characterized by disc structural damage, narrowing of joint spaces, and nerve root compression, significantly reducing patients' quality of life. To address this challenge, a novel therapeutic strategy was developed using cellulose supramolecular hydrogel as a carrier to deliver IL4I1-modified MΦ membrane biomimetic nanoparticles (CHG@IL4I1-MNPs) to target tissues. This hydrogel exhibits excellent biocompatibility and mechanical properties while enabling sustained drug release in the degenerative disc microenvironment, enhancing therapeutic outcomes. CHG@IL4I1-MNPs effectively regulate MΦ polarization by promoting M2 MΦ activation, thereby improving immune microenvironment balance. Animal studies demonstrated that CHG@IL4I1-MNPs alleviated symptoms of IDD, reduced inflammation, and supported tissue repair, highlighting its potential to reduce reliance on long-term medication and improve quality of life. The strategy uniquely combines nanoparticle technology with immunomodulation, achieving precise targeting of MΦs. Beyond IDD, this approach offers potential applications in other immune-related diseases, providing a versatile platform for nanomedicine. This study introduces an innovative method to treat IDD and advances the integration of immunotherapy and nanotechnology, offering both clinical benefits and new directions for future research. These findings hold strong potential for improving patient outcomes and expanding treatment options for related diseases.
© 2025. The Author(s).

Aortic aneurysm is a life-threatening disease caused by progressive dilation of the aorta and weakened aortic walls. Its pathogenesis involves an imbalance between connective tissue repair and degradation. CD34+ cells comprise a heterogeneous population that exhibits stem cell and progenitor cell properties. However, the role of CD34+ cells in abdominal aortic aneurysm (AAA) remains unclear. In this study, downregulated CD34 expression is observed in aneurysmal aortas from both patients and mouse models compared to that in non-dilated aortas. Furthermore, by combining Cd34-CreERT2;Rosa26-tdTomato;(Apoe-/-) lineage tracing, bone marrow transplantation, and single-cell sequencing, it is found that during AAA development, non-bone marrow CD34+ cells are activated to transdifferentiate into Periostin+ myofibroblasts, thereby contributing to the formation of fibrotic collars. Dual recombinase-based lineage tracing confirms the presence and involvement of CD34+/Periostin+ myofibroblasts in fibrotic collar formation during AAA development. Functionally, selective depletion of systemic or non-bone marrow CD34+ cells, as well as CD34+/Periostin+ myofibroblasts, by diphtheria toxin significantly exacerbates AAA progression and increases disease mortality. Mechanistically, it is identified that the PDGF-PDGFRb-PI3K axis is indispensable for Periostin+ myofibroblast generation from non-bone marrow CD34+ cells in AAA, offering a new therapeutic target for patients with AAA at a high risk of rupture.
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.