🧠 Neurobiology
Functional KCC2 expression marks an evolutionarily conserved population of early-maturing interneurons in the perinatal cortex
Using a high-resolution cortical developmental atlas and single-cell RNA sequencing, the authors identify a population of cortical interneurons that express the chloride transporter KCC2 already at embryonic stages. These early-maturing interneurons exhibit hyperpolarizing GABA responses ahead of principal neurons, revealing an evolutionarily conserved circuit element that may shape early network activity and cortical maturation.
Impact: Defines a conserved class of early-maturing interneurons that reframe our understanding of GABAergic circuit development.
Szrinivasan R et al., https://doi.org/10.1038/s41467-025-67270-x
Single-cell spatiotemporal transcriptomic and chromatin accessibility profiling in developing postnatal human and macaque prefrontal cortex
This study generates a comprehensive single-cell atlas combining gene expression, chromatin accessibility, and spatial transcriptomics for postnatal prefrontal cortex development in humans and macaques. The work delineates species-specific developmental trajectories, prolonged human PFC maturation, and identifies cell types and regulatory networks most vulnerable to neurodevelopmental and neuropsychiatric disorders.
Impact: Provides a cross-species multimodal atlas that links human-specific PFC maturation programs to cognitive function and disease risk.
Zhang J et al., https://doi.org/10.1038/s41593-025-02150-7
Multimodal mass spectrometry imaging for plaque- and region-specific neurolipidomics in Alzheimer’s disease mouse models
The authors employ multimodal mass spectrometry imaging to map lipid composition at and around amyloid-β plaques across distinct brain regions in Alzheimer’s disease mouse models. This neurolipidomic approach reveals plaque- and region-specific alterations in lipid species, offering mechanistic insights into how lipid remodeling relates to plaque formation and disease progression.
Impact: Establishes a high-resolution lipid imaging framework to dissect plaque-associated biochemical changes in Alzheimer’s disease.
Trinklein TJ et al., https://doi.org/10.1038/s41467-025-65956-w
🎯 Cancer Research
Deciphering precursor cell dynamics in esophageal preneoplasia via genetic barcoding and single-cell transcriptomics.
By combining genetic barcoding with single-cell RNA sequencing and validating with spatial transcriptomics, this study traces the lineage of esophageal preneoplastic cells. The authors identify a highly plastic progenitor-like population marked by genes such as Nfib and Qk that fuels proliferative and basal cell compartments, positioning these cells as key drivers of early tumorigenesis.
Impact: Reveals molecularly defined, spatially validated precursor cells that could serve as early biomarkers and interception targets for esophageal squamous cell carcinoma.
Jang J et al., https://doi.org/10.1073/pnas.2509534122
APOBEC3 promotes squamous differentiation via IL-1A/AP-1 signaling.
Using a genetically engineered mouse model and human urothelial carcinoma datasets, the authors show that APOBEC3 activity not only drives mutagenesis but also promotes squamous trans-differentiation in bladder cancer. Bulk, single-cell, and spatial transcriptomics pinpoint IL-1α–AP-1 signaling as the axis through which APOBEC3A fosters a highly squamous epithelial subpopulation.
Impact: Links APOBEC3A-driven mutagenesis to a specific squamous differentiation program, nominating IL-1α signaling as a therapeutically actionable node in bladder cancer.
Sturdivant MS et al., https://doi.org/10.1038/s41467-025-67033-8
CD8+ T cells in the tumor microenvironment modulate response to endocrine therapy in breast cancer.
Analyzing pre- and on-treatment biopsies from hormone receptor–positive breast cancer patients on letrozole, this study ties resistance to endocrine therapy to an immune-enriched tumor microenvironment with abundant CD8+ T cells. Spatial transcriptomics and functional assays highlight a CXCL9/10/11–CXCR3/7 signaling axis through which CD8+ T cells can paradoxically support tumor cell proliferation under estrogen-deprived conditions.
Impact: Identifies CD8+ T cell–associated CXCL11 signaling as a modulator of endocrine therapy resistance and a potential combinatorial therapy target in HR+ breast cancer.
Napolitano F et al., https://doi.org/10.1172/JCI188458
🧮 Technology & Methods Development
SIDISH integrates single-cell and bulk transcriptomics to identify high-risk cells and guide precision therapeutics through in silico perturbation.
SIDISH is a neural network framework that combines single-cell RNA-seq granularity with the scale of bulk RNA-seq using a variational autoencoder, deep Cox regression, and transfer learning. It can pinpoint high-risk cell populations, generalize to spatial transcriptomics to map them in situ, and run in silico perturbations to prioritize therapeutic targets that reduce high-risk cellular states.
Impact: Offers a unified, scalable computational platform to connect cellular risk states with clinical outcomes and simulate targeted interventions across diseases.
Jolasun Y et al., https://doi.org/10.1038/s41467-025-66162-4
Accurate imputation of pathway-specific gene expression in spatial transcriptomics with PASTA.
PASTA (PAthway-oriented Spatial gene impuTAtion) predicts unmeasured genes in spatial transcriptomics by integrating cell type identity, spatial proximity, and pathway information. Focusing on pathway-level rather than single-gene signals, the method yields more stable and biologically coherent imputations across simulated and real datasets, expanding the interpretability of targeted spatial assays.
Impact: Enhances the functional readout of targeted spatial transcriptomics by robustly inferring pathway activities at high spatial resolution.
Li R et al., https://doi.org/10.1038/s41467-025-67421-0
SpatialRNA: a Python package for easy application of Graph Neural Network models on single-molecule spatial transcriptomics dataset.
SpatialRNA is a Python toolkit that streamlines the generation of (sub)graphs from image-based spatial transcriptomics data and interfaces seamlessly with PyG for graph neural network modeling. It scales to the vast number of detected transcripts in single-molecule datasets, enabling efficient identification of spatial domains and molecular microenvironments with comprehensive tutorials for users.
Impact: Lowers the barrier for applying GNNs to spatial transcriptomics, accelerating discovery of spatial niches and tissue organization patterns.
Lyu R et al., https://doi.org/10.1093/bioinformatics/btaf659
🧬 Immunology & Tumor Microenvironment
CD8+ T cells in the tumor microenvironment modulate response to endocrine therapy in breast cancer.
Analyzing paired biopsies before and during estrogen deprivation, the study reveals that endocrine therapy–resistant HR+ breast tumors harbor increased stromal TILs, interferon-γ signaling, and enriched CD8+ T cell infiltration. Spatial and functional analyses implicate CXCL11 produced in the tumor–T cell crosstalk as a driver of cancer cell proliferation in estrogen-free conditions via CXCR3/CXCR7.
Impact: Illuminates how specific CD8+ T cell–chemokine interactions in the TIME can counteract endocrine therapy, informing rational immune–endocrine combination strategies.
Napolitano F et al., https://doi.org/10.1172/JCI188458
🫀 Fibrosis & Regeneration
Clusterin Drives Fiber Endocytosis by Mesothelial Cells to Resolve Liver Fibrosis.
This work investigates the role of the secreted glycoprotein clusterin (CLU) in liver fibrosis, a typically irreversible outcome of chronic liver disease. The authors show that CLU promotes endocytosis of fibrotic fibers by mesothelial cells, uncovering a previously unappreciated pathway that can facilitate fibrosis resolution.
Impact: Identifies clusterin-driven mesothelial fiber clearance as a promising therapeutic mechanism to reverse established liver fibrosis.
Wang M et al., https://doi.org/10.1053/j.gastro.2025.08.022