Cell Reports

MRAP2 potentiates GPCR signaling by conserved mechanisms that are disrupted by obesity-associated genetic variants Jamaluddin et al. investigated how the MRAP2 accessory protein enhances signaling by three appetite-regulating GPCRs. MRAP2 disrupts GPCR oligomerization to form interactions, and its cytoplasmic region is essential for signaling. MRAP2 variants modulate receptor constitutive activity, enhance internalization, and reduce signaling, contributing to weight gain and hyperglycemia observed in humans.

MRAP2 potentiates GPCR signaling by conserved mechanisms that are disrupted by obesity-associated genetic variants

Ca2+-phospholipid-dependent regulation of Munc13-1 is essential for post-tetanic potentiation at mossy fiber synapses and supports working memory López-Murcia et al. demonstrate that Ca2+-dependent regulation of the vesicle-priming protein Munc13-1 supports synaptic short-term facilitation and post-tetanic potentiation at hippocampal mossy fiber synapses. Disruption of this regulatory mechanism is associated with impaired working memory formation.

Ca2+-phospholipid-dependent regulation of Munc13-1 is essential for post-tetanic potentiation at mossy fiber synapses and supports working memory

In utero exposure to NMDA receptor autoantibodies disrupts hippocampal circuit maturation Majoros, Zhang, and Rahmati et al. identify a link between maternal autoimmunity and disrupted neuronal network development in the hippocampus of mice. In utero exposure to NMDA receptor autoantibodies impairs GABAergic signaling and early network synchrony in neonates, hindering the emergence of continuous hippocampal activity around eye opening.

In utero exposure to NMDA receptor autoantibodies disrupts hippocampal circuit maturation

Assembly and annotation of hexaploid Sesuvium portulacastrum genome reveals insights into ion transport-mediated high-salinity adaptation Yuan et al. report a high-quality chromosome-scale genome of the hexaploid halophyte Sesuvium portulacastrum. Comparative genomics and transcriptomics provide insights into its salt-adaptation evolution and identify the key salt-tolerant gene SpHAK3, offering genetic resources for improving crop tolerance.

Assembly and annotation of hexaploid Sesuvium portulacastrum genome reveals insights into ion transport-mediated high-salinity adaptation

Small-molecule enhancement of METTL3 S-palmitoylation as a therapeutic strategy for osteoarthritis METTL3 undergoes S-palmitoylation, which promotes cytoplasmic phase separation to facilitate mRNA translation and maintain its stability. We identify a small molecule that enhances this modification, providing a mechanistic basis for a potential osteoarthritis therapy.

Small-molecule enhancement of METTL3 S-palmitoylation as a therapeutic strategy for osteoarthritis

Clec16a maintains definitive hematopoietic stem and progenitor cells via mitophagy Cai et al. identify the E3 ubiquitin ligase CLEC16A as a conserved regulator of embryonic hematopoiesis. CLEC16A maintains the endothelial-to-hematopoietic transition by stabilizing ATG5 and promoting mitophagy, thereby balancing mitochondrial ROS and maintaining hematopoietic fate determination.

Clec16a maintains definitive hematopoietic stem and progenitor cells via mitophagy

ACSL4-associated lipid metabolism is a distinct therapeutic vulnerability in KMT2A-rearranged acute myeloid leukemia Schäfer et al. identify ACSL4 as a selective vulnerability in KMT2A-rearranged AML. ACSL4 knockdown impairs leukemic growth in vitro and in vivo by reprogramming lipid metabolism, which can be rescued by polyunsaturated fatty acids (PUFAs). A KRADS12 signature derived from ACSL4-dependent cells is associated with poor patient survival.

ACSL4-associated lipid metabolism is a distinct therapeutic vulnerability in KMT2A-rearranged acute myeloid leukemia

Glomerular basement membrane structural integrity dictates trans-tissue deposition of laminin in the kidney Omachi and Lin et al. uncover an unexpected source of ectopic laminin-α2 deposition in the glomerular basement membrane in Alport syndrome. They show that laminin-α2 circulates in blood and deposits according to basement membrane integrity, revealing a trans-tissue route for extracellular matrix deposition in mammals.

Glomerular basement membrane structural integrity dictates trans-tissue deposition of laminin in the kidney

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Local heterochromatin enrichment promotes telomere clustering and PML nuclear body assembly at telomeres Telomeres in ALT-positive cancers display reduced nucleosome density yet retain heterochromatin-associated factors. This study shows that telomeric heterochromatin drives telomere clustering and PML nuclear body assembly, while ATRX and DAXX suppress this process, establishing a role for telomeric chromatin in mediating ALT-associated subnuclear compartmentalization of telomeres.

Local heterochromatin enrichment promotes telomere clustering and PML nuclear body assembly at telomeres

Heterogeneity and plasticity of the naive CD4+ T cell compartment Sajani et al. describe the transcriptional heterogeneity of murine and human naive CD4+ T cells as comprising multiple discrete clusters that impact CD4+ T cell fate and trajectories. Naive CD4+ T cells experiencing inflammatory environments exhibit an altered transcriptional state that biases their differentiation trajectories.

Heterogeneity and plasticity of the naive CD4+ T cell compartment

Glutamine metabolism tunes myeloid responses to drive resolution of inflammation during skin repair Xu et al. uncover how metabolites regulate cellular communication during inflammatory resolution and tissue repair in vivo. They find that glutamine metabolism alters chromatin accessibility and suppresses neutrophil chemotaxis gene transcription to resolve inflammation and drive tissue repair.

Glutamine metabolism tunes myeloid responses to drive resolution of inflammation during skin repair

Identification of endometrial CD169+ macrophages essential for Treg cell accumulation and implantation Successful implantation requires timely endometrial accumulation of regulatory T (Treg) cells. Ohki et al. characterize tissue-localized CD169+ macrophages that express Treg cell-recruiting chemokines, including CCL8. Depleting these macrophages reduces uterine Treg cell accumulation and impairs implantation, with related CD169+ macrophages observed in human endometrium.

Identification of endometrial CD169+ macrophages essential for Treg cell accumulation and implantation

Universal gene-level bimodality in natural microbial communities Hong et al. uncover widespread bimodal gene abundance across microbiomes and show that these genes mark niche-specific functions. Their gene-centric typing approach identifies gut bimodal genes that predict disease, offering insights into microbiome functional architecture and diagnostic applications.

Universal gene-level bimodality in natural microbial communities

Dual roles of USP39 in stabilizing PB2 and orchestrating ribonucleoprotein assembly drive H5 influenza virus replication and pathogenicity Yang et al. identify USP39 as a deubiquitinase hijacked by H5 AIV. USP39 catalytically deubiquitinates PB2 to prevent its degradation and maintain polymerase activity. Meanwhile, it promotes PB2-PB1 association for RNP assembly. The dual-function mechanism facilitates viral replication, enhances pathogenicity, and represents a promising anti-H5 therapeutic target.

Dual roles of USP39 in stabilizing PB2 and orchestrating ribonucleoprotein assembly drive H5 influenza virus replication and pathogenicity

Compound amino acid synergizes ceftazidime-avibactam to eradicate extracellular and facultative intracellular MDR pathogens This study demonstrates that the FDA-approved drug 18AA potently resensitizes multidrug-resistant pathogens to ceftazidime-avibactam. It achieves this by activating two bacterial pathways, the inosine-CusS/R-CusC axis and the proton motive force, to promote antibiotic influx, offering a readily translatable strategy against formidable infections.

Compound amino acid synergizes ceftazidime-avibactam to eradicate extracellular and facultative intracellular MDR pathogens

Evolutionary-guided advanced deep-learning architecture powers mammalian GPCRome agonist predictions Mittal et al. present EvOlf, a deep‑learning framework that integrates odorant and non‑odorant GPCRs across species to predict ligand‑receptor interactions. The model outperforms existing methods, identifies novel allosteric modulators, and offers a scalable platform for GPCR deorphanization.

Evolutionary-guided advanced deep-learning architecture powers mammalian GPCRome agonist predictions

Adenosine signaling driven by the gut microbiota underlies chronic alcohol-induced anesthetic resistance Wang et al. demonstrate that long-term alcohol consumption diminishes anesthetic sensitivity via a gut-microbiome-brain pathway. Their findings indicate that alcohol-induced dysbiosis elevates the metabolite adenosine, which subsequently downregulates brain GABAA receptors, thereby compromising anesthetic effectiveness.

Adenosine signaling driven by the gut microbiota underlies chronic alcohol-induced anesthetic resistance

PCIF1-mediated m6Am modification in ACC neurons participates in inflammatory pain and anxiety Liu et al. demonstrate that the m6Am methyltransferase PCIF1 in ACC neurons is crucial for both the initiation and maintenance of inflammatory pain and comorbid anxiety. They further reveal that PCIF1 modulates these behaviors by targeting Gap43 m6Am modification, thereby promoting GAP43 expression.

PCIF1-mediated m6Am modification in ACC neurons participates in inflammatory pain and anxiety

A single-cell transcriptional reference for the functional and developmental diversity of neonatal innate lymphoid cells This study dissects the transcriptional diversity of circulating innate lymphoid cells (cILCs) from umbilical cord blood on the single-cell level. Accompanying phenotypic, functional, and differentiation experiments establish cILC1s as restricted NK cell progenitors and identify an IFNγ-producing cILC3 subset that is responsive to stimulation via the CD28 pathway.

A single-cell transcriptional reference for the functional and developmental diversity of neonatal innate lymphoid cells

Proteotranscriptomic classification and characterization of pancreatic neuroendocrine neoplasms (Cell Reports 37, 109817; October 12, 2021)

Proteotranscriptomic classification and characterization of pancreatic neuroendocrine neoplasms

NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma (Cell Reports 41, 111623; November 8, 2022)

NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma

Electroacupuncture suppresses premature ventricular complexes occurring post-myocardial infarction through corticothalamic circuit (Cell Reports 45, 116734; January 27, 2026)

Electroacupuncture suppresses premature ventricular complexes occurring post-myocardial infarction through corticothalamic circuit

CGRP signaling links tumor-associated pain to immune evasion in oral squamous cell carcinoma McIlvried et al. report an inverse relationship between patient-reported pain and tumor-infiltrating lymphocytes in patients with oral cancer. Using gain- and loss-of-function approaches in syngeneic mouse models, they establish that tumor-evoked nociceptor activation drives CGRP-mediated immunosuppression. They then show that CGRP receptor antagonism reduces both tumor-associated pain and immune evasion.

CGRP signaling links tumor-associated pain to immune evasion in oral squamous cell carcinoma

Insulin-like growth factor signaling regulates zebrafish lymphatic-vessel development Chen et al. have discovered that IGF signaling acts locally to promote the migration of a lymphatic vessel along the craniofacial cartilage. They also demonstrate that IGF1R signaling promotes both zebrafish and human lymphatic cell migration, indicating that IGF signaling has a conserved role in lymphatic-vessel development.

Insulin-like growth factor signaling regulates zebrafish lymphatic-vessel development

In vivo modeling of human γδ T cell ontogeny reveals terminal deoxynucleotidyl transferase as a key regulator of type 3 Vδ2 T cell development Human γδ T cells differ greatly from mouse γδ T cells. La et al. report that it is possible to generate bona fide human γδ T cells in a humanized immune system mouse model. Additionally, they show that TdT controls the development of type 3 Vδ2 T cells.

In vivo modeling of human γδ T cell ontogeny reveals terminal deoxynucleotidyl transferase as a key regulator of type 3 Vδ2 T cell development

Liquid-liquid phase separation of EphB4 drives pulmonary hypertension via YAP activation Liu et al. reveal that vascular stiffening drives pulmonary hypertension by inducing EphB4 to undergo phase separation in smooth muscle cells. These condensates trap YAP inhibitors, unleashing pathogenic proliferation. A targeted peptide disrupts condensation and attenuates pulmonary hypertension in vivo, revealing a new mechanotherapeutic strategy.

Liquid-liquid phase separation of EphB4 drives pulmonary hypertension via YAP activation

Genomic foundations of salt tolerance in desert cyanobacteria Ye et al. uncover the genetic changes enabling a desert cyanobacterium to thrive in hypersaline soils through genomic, evolutionary, and functional analyses, and reveal how structural rearrangements, key pathway collaboration, and important amino acid accumulation collectively underpin extreme environmental adaptation.

Genomic foundations of salt tolerance in desert cyanobacteria

Single-cell multi-omic analyses highlight the essential role of NKX2.2-CLEC16A/endosomal pathway for human pancreatic differentiation and function Chen et al. provide a comprehensive roadmap of the gene regulatory networks governing human pancreatic differentiation and identify the essential roles of the NKX2.2-CLEC16A/endosomal pathway axis for islet organogenesis. This study also highlights the expandable pancreatic progenitor (ePP)-islet system as a powerful platform for investigating cell fate decisions and disease modeling.

Single-cell multi-omic analyses highlight the essential role of NKX2.2-CLEC16A/endosomal pathway for human pancreatic differentiation and function

Nuclear import of malaria RNA rewires splicing in host immune cells Abou Karam et al. identify a cell communication mechanism used by the malaria parasite Plasmodium falciparum. The parasite delivers its mRNAs into monocytes and imports them into their protected nuclei, where they perturb the splicing. This extracellular RNA-based strategy disrupts host transcript processing and immune signaling, revealing another layer of host interference.

Nuclear import of malaria RNA rewires splicing in host immune cells