Biology subjects

Zhou, L.

Publications and source records attributed to Zhou, L..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

OmicOS: A Comprehensive Omics Ecosystem Infrastructure and Agent System for the AI Era

Biology has accumulated a vast ecosystem of omics methods, but much of this ecosystem remains built for expert humans rather than scientific agents. Methods are scattered across Python packages, R/Bioconductor and CRAN workflows, command-line tools, incompatible data containers and implicit object states, making even routine analyses difficult for an AI system to choose, execute and verify reliably. Here we introduce OmicOS, a comprehensive omics ecosystem infrastructure and agent system that turns OmicVerse V2, an open-source omics community, into an executable foundation for agentic biology. OmicVerse V2 provides the community substrate: scalable AnnDataOOM-compatible rust backends, agent-friendly Python algorithms for single-cell, spatial, bulk and multi-omics analysis, interfaces to single-cell foundation models, and Python-native reconstructions of historically R-centred Bioconductor/CRAN-style workflows. OmicOS makes this substrate actionable by registering analytical functions as state-aware capability contracts, allowing agents to inspect live data objects, select valid methods, execute controlled workflows and record provenance. The result is not a fixed pipeline, but a programmable omics environment in which agents compose real analyses from verified community methods rather than inventing tools. Across external and purpose-built benchmarks, OmicOS ranked first among the evaluated systems, reaching 81.2% on BiomniBench. Adding OmicVerse to a minimal agent improved task completion by up to 34.2 percentage points with qwen-3.6-35b, and controlled ablations showed that the gains came from registry-grounded execution rather than from larger models, documentation retrieval or unrestricted tool exposure. The same infrastructure scaled to atlas-sized data, reproduced R-centred workflows in Python and converted external pathology software into agent-usable skills. In a discovery task starting from a whole-body spatial map and the term "Alzheimers disease", OmicOS composed a non-canonical workflow that integrated spatial expression, genetic association, eQTL and colocalization evidence to nominate a colon epithelial risk axis centred on PICALM, CD2AP and CR1. Together, OmicVerse and OmicOS define an open foundation for AI-era omics, showing how a community of biological methods can be transformed into a reliable, extensible and agent-operable system for discovery. HighlightO_LIOmicVerse 2.0 consolidates 694 methods spanning 11 omics domains into agent-callable high-level APIs. C_LIO_LIRebuildR automatically reconstructs and evolves R/Bioconductor methods as Python-native implementations under output-equivalence gates. C_LIO_LIOmicOS establishes a state-of-the-art omics agent harness, ranking first on general omics benchmarks across models and substantially improving the analytical capability of local open-source models. C_LIO_LICompositional use of ecosystem modules nominates a colon epithelial axis associated with Alzheimers disease risk. C_LIO_LIExternal algorithm packages supporting automatic iterative evolution can be integrated into the OmicOS ecosystem. C_LI

bioinformatics↗

bioRxiv2026

Broad Sarbecovirus Neutralization by an S2-Directed Plasma Antibody Defines a New Site of Vulnerability in SARS-like Viruses

The repeated emergence of pathogenic coronaviruses highlights the continual threat of zoonotic spillover events and the need to understand conserved regions of the viral spike protein that influence immune recognition. Here, we employ high-resolution proteomic analysis of circulating immunoglobulins to characterize the antibody response to the SARS-CoV-2 spike protein in vaccinated and infected individuals. We recombinantly expressed abundant plasma IgG lineages and identified nine antibodies targeting the highly conserved S2 spike subunit. Most of these S2-reactive plasma mAbs (7 of 9) exhibited neutralizing activity against pangolin coronavirus, while one mAb (SC45) demonstrated potent (IC50 < 1 {micro}g/mL) neutralizing activity against both pangolin and bat sarbecoviruses RsSHC014 and WIV1. Additionally, SC45 exhibited potent prophylactic efficacy in the K18-hACE2 mouse model challenged with Pangolin-Guangdong CoV MP789 (Pg-CoV), significantly reducing lung viral replication at day 4 post-infection. The cryo-EM structure of SC45 bound to the prefusion-stabilized S2 domain of Pg-CoV reveals that SC45 targets a novel, conserved epitope in the connector domain. Strikingly, even though SC45 was the most abundant antibody ([~]13%) of anti-spike plasma IgG in an infected patient and binds to both SARS-CoV-2 and Pg-CoV spike with comparable affinities, it fails to neutralize early (D614G and Omicron BA.1) SARS-CoV-2 variants. Together, these findings identify a conserved site of vulnerability in the spike S2 subunit which informs on potential mechanisms of antibody immunity to zoonotic coronaviruses.

immunology↗

bioRxiv2026

Hypertension is related to a slower radiotracer removal from lateral ventricles

BackgroundImpairment of brain waste removal contributes to Alzheimers disease etiology and progression. Although hypertension is a risk factor for dementia, little is known about how it affects measures of clearance in human brain. MethodsCross-sectional (n=159) and longitudinal (n=94) analysis of the relationship between blood pressure (BP) and brain clearance. The estimate of brain clearance was measured using positron emission tomography (PET) as the rate of radiotracer (MK-6240) efflux from the lateral ventricles in the 10-30-minute window after tracer injection. We also examined cerebral blood flow, PET-derived tau deposition in the medial temporal lobe, cognition and plasma biomarkers of neurodegeneration. At baseline we compared participants with (n=88) and without (n=71) hypertension. For longitudinal analyses we defined two groups based on systolic BP trajectories from baseline to follow-up: as long-term controlled (n=76) or uncontrolled BP (n=18). ResultsAt baseline, subjects with hypertension had lower ventricular clearance than normotensive controls (Cohens d=0.53, p=0.001). Over the course of the observation period (median 1.85 years) subjects in the uncontrolled BP group experienced a steeper reduction in clearance rates ({beta}=-5.88) than subjects in the controlled BP group ({beta}=-0.81, interaction p=0.039). ConclusionsOur study suggests that hypertension impairs brain clearance of fluids.

neuroscience↗

bioRxiv2026

Hapln1-HA signaling promotes progenitor cell proliferation and spinal cord regeneration

Adult zebrafish exhibit scarless repair and functional recovery following spinal cord injury. Their regenerative capacity is attributed to potent stem-like progenitors that mediate neuronal and glial repair. Zebrafish are thought to lack anti-regenerative extracellular matrix (ECM) components abundant in mammalian SCI, but the positive contributions of ECM to spontaneous spinal cord repair are less understood. By employing cross-species single-cell transcriptomics, we found the hyaluran modifying enzyme Hapln1 is upregulated in zebrafish progenitors but not in mouse progenitors following injury. Loss-of-function of hapln1a/b and ablation of hapln1+ cells reduce progenitor cell activation and hinder spontaneous recovery from injury. Using a series of in vivo and in vitro assays, we show that Hapln1 is required for hyaluran-cd44b mediated progenitor cell proliferation. This study reveals that, in addition to lacking anti-regenerative ECM components around SC lesions, zebrafish can also leverage pro-regenerative ECM molecules to enhance progenitor cell potency and promote repair.

neuroscience↗

bioRxiv2026

Assessing alternative methods of using population genomic data to measure changes in population size

Malaria remains a major global health burden, with traditional control methods facing challenges such as insecticide resistance and high operational costs. Genetic biocontrol offers a promising alternative for mosquito population suppression, but its field efficacy would require assessment. This study evaluates the role that population genomic statistics can play in detecting decreases in population size in the context of a cluster randomized control trial (cRCT), investigating the response of nucleotide diversity ({pi}), Tajimas D, segregating sites, and linkage disequilibrium (LD) under both constant and seasonal demographic scenarios. We simulated 90% and 99% population declines with various degrees of between-cluster heterogeneity, and assessed the detection power of each statistic over time and number of clusters per arm. Results show that Tajimas D is highly sensitive and robust across crash severity, seasonality and heterogeneity scenarios. Segregating sites has similar power to Tajimas D when baseline data are available. We further estimated that cRCTs require approximately 3 to 5 villages per treatment arm to achieve adequate statistical power. These findings provide recommendations for genetic monitoring of vector control interventions in wild populations.

evolutionary biology↗

bioRxiv2026

Hyperactive STAT1 Promotes T Follicular Helper Type 1 Cell Differentiation to Trigger Autoimmunity

ABSTRACTSHeterozygous gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause an inborn error of immunity characterized by immune dysregulation, recurrent infections and various autoimmune manifestations. However, the precise pathogenic mechanism by which STAT1 GOF contributes to autoimmunity remains elusive. In our cohort, STAT1-GOF patients exhibit biased circulating follicular helper T (cTfh) populations with CXCR3+ Tfh1-like features. Using a Stat1 GOF mouse model that spontaneously developed autoimmunity, we found that overactivated STAT1 promotes Tfh differentiation and disrupted T cell-dependent humoral responses with skewed immunoglobulin class switching towards IgG2. Furthermore, STAT1 GOF directly targets to Tfh and Th1 cell signature genes and thereby drives the development of Tfh1 cells with excessive IFN-{gamma} production, which implicated in autoantibody production and the development of autoimmunity. Notably, IFN-{gamma} neutralization significantly alleviated autoimmune cellular responses and autoantibody levels in mutant mice, highlighting IFN-{gamma} blockade as a promising targeted therapy for the STAT1-GOF patients with autoimmunity. Our findings suggest that proper regulation of STAT1 activity within a reasonable magnitude is crucial for ensuring optimal host-protective humoral immunity. One-sentence summaryOveractivated STAT1 promotes Tfh1 differentiation to drive autoimmunity.

immunology↗

bioRxiv2026

Sleeve gastrectomy protects lean mice from future obesity.

BackgroundObesity and metabolic disease drive premature aging and reduced lifespan. While metabolic interventions like calorie restriction, protein restriction, and time restricted feeding have been shown to improved lifespan, they are either not effective or sustainable for most humans. Bariatric surgery is the most efficacious metabolic intervention available and is associated with increased lifespan. However, whether its longevity benefits derive solely from weight reduction or reflect surgery-specific metabolic reprogramming remains unknown. MethodsWe employed a lean mouse model of sleeve gastrectomy (SG) in which young, lean male C57BL/6J mice underwent SG or sham operation while maintained on low-fat chow, then were challenged with high-fat diet (HFD) in midlife. We assessed glucose metabolism, body composition, energy expenditure, hepatic histology, adipose tissue inflammation, and cecal microbiome composition. ResultsDespite identical weight and food intake on low-fat chow, SG mice demonstrated improved glucose tolerance and insulin sensitivity prior to HFD challenge. Upon HFD exposure, SG animals exhibited enhanced metabolic flexibility with greater capacity for fat oxidation, increased energy expenditure, attenuated weight gain, and reduced adiposity compared to sham controls. SG further reduced hepatic lipid accumulation and attenuated visceral adipose tissue inflammation, marked by decreased pro-inflammatory cytokine expression and reduced macrophage infiltration. These metabolic benefits occurred independently of caloric intake. Cecal microbiome profiling revealed surgery-specific remodeling characterized by Lactobacillus enrichment and reductions in Verrucomicrobia and Clostridia -- a pattern distinct from caloric restriction and consistent with prior SG studies. ConclusionsEarly-life SG confers durable, weight-loss-independent protection against midlife metabolic deterioration. Gut microbiome remodeling, particularly enrichment of Lactobacillus species, represents a candidate mediating mechanism and a potential therapeutic target for aging and metabolic disease.

physiology↗

bioRxiv2026

A systemic circadian nicotinic acid riboside (NaR) signal engages the unfolded protein response and adipogenesis via the prefoldin complex

Daily light-dark cycles impose predictable environmental fluctuations that require coordinated temporal regulation of cellular physiology. This coordination is mediated by the circadian clock, which operates as a network of tissue oscillators; however, the molecular signals that convey circadian information between organs remain incompletely defined. Here, we identify nicotinic acid riboside (NaR) as a circulating metabolite whose rhythmicity depends on the liver clock. In differentiating 3T3-L1 adipocytes, NaR engages unfolded protein response (UPR) gene programs and modulates adipogenic competence. Proteome-wide stability profiling implicates the prefoldin complex as a molecular target of NaR signaling, linking NaR exposure to altered proteostasis. Functionally, NaR-induced UPR signaling converges on the adipogenic transcription factor CEBPA, which is a central regulator of adipogenesis. Importantly, sustained NaR exposure suppresses adipocyte lipid deposition, whereas temporally restricted NaR stimulation enhances adipogenesis, indicating that NaR acts in a time-dependent manner. Together, these findings identify NaR as a liver clock-controlled circulating metabolite that couples systemic circadian metabolism to adipocyte proteostasis and differentiation, revealing a mechanism by which temporal metabolic signals shape tissue-specific physiological outcomes. HighlightsO_LIThe circadian clock is required for rhythmic regulation of circulating nicotinic acid riboside (NaR). C_LIO_LIThe liver clock is sufficient to generate NaR rhythmicity. C_LIO_LINaR engages the prefoldin complex to regulate unfolded protein response signaling and Cebpa expression. C_LIO_LITime-dependent NaR exposure differentially regulates CEBPA levels and adipocyte lipid deposition. C_LI

systems biology↗

bioRxiv2026

Information Geometry Reconciles Discrete and Continuous Variation in Single-Cell and Spatial Transcriptomic Analysis

Single-cell and spatial transcriptomics provide high-resolution cellular characterization, yet standard analytical approaches remain theoretically misaligned with the probabilistic nature of the data. After UMI normalization, current pipelines rely on Euclidean or log-transformed Euclidean distance for similarity measurement. Both are fundamentally ill-suited to model the multinomial count data. Euclidean distance in normalized space overemphasizes high-variance genes, while log-transformation inverts this bias but at the cost of distorting subtle, continuous expression modulations. Neither approach naturally captures the dual nature of gene expression: both discrete presence/absence transitions and continuous quantitative variation. To overcome these limitations, we introduce GAIA (Geometric Analysis from an Information Aspect), an information-geometric framework for cell representation learning and inter-cell similarity measurement. By anchoring analysis in the true probabilistic model, treating cells as multinomial distributions over genes and projecting cells to a statistical manifold, GAIA organically reconciles both the presence/absence effect and the more continuous expression modulations. Mathematically, GAIA exploits the equivalence between Fisher-Rao distance in multinomial space and geodesic distance on the unit hypersphere, a property that enables both theoretical guarantees and computational efficiency. Experiments in synthetic and real scRNA-seq and spatial transcriptomic datasets demonstrate that GAIA preserves robust and consistent cell-to-cell relationships, delineates biologically nuanced sub-types, mitigates batch effects arising from sequencing depth variation, and eliminates the dependence on knowledge-restricted gene selection for learning meaningful cell representations. Overall, GAIA offers a knowledge-lean, variance-stabilizing framework for analyzing single-cell and spatial transcriptomic data, enhancing discrimination between nuanced cell sub-type and -states.

bioinformatics↗

bioRxiv2026

Spinal cord regeneration deploys adult molecular programs that do not recapitulate embryonic development

Adult zebrafish reverse paralysis after spinal cord injury. Their regenerative capacity is stem cell-dependent and often attributed to potent progenitors that retain embryonic radial glial features and reenact developmental programs after injury. To explore the extents to which regeneration recapitulates development, we integrated single-cell RNA-sequencing datasets spanning development, adult homeostasis and adult regeneration. We found immune cell maturation and neuronal differentiation extend into the juvenile stages, while only 25% of injury-responsive adult progenitors recapitulate larval progenitor identities. By annotating larval progenitors based on their dorso-ventral identities and chronological age, we inferred the spatio-temporal features of adult sox2+ progenitors. This analysis showed the dorso-ventral progenitor identities that guide spinal cord development are not faithfully maintained in homeostatic or regenerating adults. This study reports a genome-wide, single-cell examination of similarities and differences between development and regeneration and indicates adult tissue regeneration repurposes developmental pathways into newly acquired regenerative functions rather than recapitulating development.

developmental biology↗

bioRxiv2026

Cell Type Architecture and Positional Gene Gradients in an Adult Animal at Subcellular Resolution

The spatial organization of cell types and gene expression underlies tissue architecture and organismal physiology. However, resolving complete cellular and molecular landscapes within a three-dimensional context remains challenging, particularly in organisms with high cellular heterogeneity and complex geometry. Here, we developed a semi-supervised workflow to reconstruct high-resolution three-dimensional spatial transcriptomic models of the planarian Schmidtea mediterranea at single-cell resolution. Planarians are basal bilaterians capable of regenerating body structures after injury. Our reconstruction maps the distribution of cell types and spatially patterned gene expression across the intact organism and identifies 119 candidate positional control genes (PCGs). These genes are expressed across muscle, neural, and epidermal populations. Functional perturbation of selected candidates, including pitx3, ptpn11, pi4ka, upf3b, and cul1, revealed roles in regeneration following injury. In addition, we identify intestinal cells as prominent components of the microenvironment surrounding adult tgs1 pluripotent stem cells (neoblasts). Together, these results demonstrate the utility of three-dimensional spatial transcriptomic reconstruction for mapping cellular architecture and positional gene regulation in complex adult organisms.

developmental biology↗

bioRxiv2026

4D Single-Cell Spatial Transcriptomics Reveals Dynamic Morphogenetic Gradients and Regenerative Domains in Planarians

Regeneration relies on precise spatiotemporal gene expression and cellular responses to establish tissue identity and body patterning. Using high-resolution Stereo-seq (715 nm) on 353 sections from 16 whole animals at 8 regeneration timepoints, we constructed a 4D spatiotemporal transcriptomic map of planarian regeneration. Our analysis captured 36 refined cell types from 3,508,004 segmented cells, enabling genome-wide transcriptional imputation of gene expression dynamics across body axes at cellular, tissue, and organismal scales. We identified dynamic positional gradients and distinct spatially distributed cell types during regeneration, including an injury-induced Anterior Regenerative Zone (ARZ). The ARZ exhibited enriched positional signals in epidermal, muscle, and neural cells and was regulated by Mediator 8, which is crucial for polarity remodeling and blastema formation. This study provides a comprehensive spatial molecular and cellular map of regenerative processes, highlighting injury-induced spatial domains and key regulatory factors in planarian regeneration. We also provide an interactive web portal, offering a valuable resource for exploring and analyzing regeneration mechanisms in a spatiotemporal context.

developmental biology↗

bioRxiv2026

Sparse mixed codes on shared manifolds for human-like spatial attention in artificial neural networks

Spatial attention is often partitioned into endogenous, exogenous, and social forms, yet it remains unclear whether a single neural circuit can support all three and how their population codes are organized. Here we trained recurrent artificial neural networks (ANNs) with convolutional sensory front-ends on three classic cueing paradigms (central, peripheral, and gaze cues) to reproduce human reaction time (RT) profiles across cue-target onset asynchronies. Despite differences in sensory architecture and visual experience, all ANNs captured the full facilitation-inhibition time course for all three attention types. Model-based targeted dimensionality reduction (mTDR) revealed that cue- and choice-related activity in the advanced cognitive module evolved as rotations within a shared low-dimensional manifold, with angular deflections that mirrored the distinct temporal dynamics of endogenous, exogenous, and social attention. Attentional signals were encoded by highly sparse, distributed population activity: a small subset of recurrent units explained most task-related variance, was sufficient to recover human-like RT patterns after virtual lesioning, and became progressively sparser as training improved performance. At the same time, single unit responses displayed pervasive mixed selectivity, dominated by nonlinear conjunctions of cue type, cue direction, and validity, whose strength and heterogeneity robustly predicted model performance. Together, these results identified low-dimensional geometric rotations, sparse coding, and nonlinear mixed selectivity as core computational principles through which a single recurrent circuit could generate human-like temporal dynamics across endogenous, exogenous, and social orienting, and provided testable predictions for population-level mechanisms of spatial attention in the brain.

neuroscience↗

bioRxiv2026

Transient activation of potent progenitor cells is required for spinal cord regeneration

Adult zebrafish exhibit full recovery following spinal cord injury. Transient expansion of stem cell-like progenitors is thought to underlie their regenerative capacity. Yet, our understanding of the identities and contributions of the crucial stem cell populations that direct spontaneous neural repair remains limited. Moreover, while most neural regeneration research is centered on promoting proliferative repair, the regulatory mechanisms that reinstate quiescence post-repair are unknown. Here, we determined the molecular identities and cellular contributions of sox2+ progenitors during spinal cord repair. Genetic lineage tracing shows zebrafish spinal progenitors, while quiescent in uninjured tissues, self-renew and differentiate into neurons and glia after injury. By single-cell sequencing, sox2+ cells are heterogeneous and biased towards neuronal or glial fates in both homeostatic and regenerating tissues. By screening for transcription factors that are differentially expressed in acute versus chronic spinal cord injury, we find the Bach1 transcription factors control transient progenitor cell activation by acting as dual activators and repressors of sox2 expression. This study elucidates the molecular diversity and contributions of sox2 expressing cells during spinal cord repair and identifies a transcriptional regulatory switch by which progenitor cells expand after injury and restore quiescence after regeneration is completed.

neuroscience↗

bioRxiv2026

immgenT: A Comprehensive Reference of Convergent T-cell States in the Mouse

The immgenT collaborative project generated a comprehensive molecular atlas of T cells spanning virtually all mouse organs and disease states, profiling ~800,000 cells from 750 samples with RNA, 128-plex surface protein, and {beta}TCR sequence. Applying a deep generative model to joint RNA and protein data defined the landscape of T-cell states organized into eight lineages and 107 robust clusters, integrating similar cells from different contexts, and resolving prior nomenclatures. Analysis of effector molecules, transcription factors and modules showed that both immunological functions and regulatory programs are shared across cell states. This framework provides a stable, reusable reference, demonstrated by computationally integrating 16 external datasets from diverse biological contexts. A set of public web tools supports browsing of these data and mapping of any dataset onto the immgenT framework. These results propose a molecular classification of T cells organized around a set of shared states reused across immunological contexts.

immunology↗

bioRxiv2026

Genome Position Does Not Impact Transgene Expression Efficiency in the Ancient Red Alga Cyanidioschyzon merolae

The thermoacidophilic red alga Cyanidioschyzon merolae represents one of the simplest photosynthetic eukaryotes and an ancient divergent group in the primary endosymbiotic Viridiplantae. Because of its [~]16 Mbp genome, containing few introns, and capacity for transgene integration by homologous recombination, it is an emerging chassis for synthetic biology. However, genomic integration sites and scalable transformation methods have not been established to systematically investigate the effect of genome position on transgene expression. Here, we combined bioinformatic genome analysis, liquid-handling robotics, and assays of heterologous protein and metabolite production to establish a reproducible framework for nuclear genome engineering in C. merolae. We mapped and annotated 40 intergenic loci as candidate neutral sites across 16 out of 20 chromosomes and could validate 38 of them through robotic-assisted transformation. Reporter gene expression analysis revealed highly uniform expression at all integration sites across broad populations of transformants, indicating surprising minimal positional effects and transcriptional neutrality. The functional equivalence of these genomic landing pads was determined by expression of a heterologous isoprene synthase, and coupling algal photobioreactors to headspace analysis to quantify isoprene production driven by transgene expression from different integration sites. Single copy transgene integrants, regardless of genome position, exhibited comparable reporter signals and consequent isoprene production. Together, these results provide the first experimentally validated set of neutral integration sites in C. merolae and establish a high-throughput transformation protocol for its genetic engineering in the context of synthetic genome biology.

synthetic biology↗

bioRxiv2026

Structural basis of underwound DNA topology bearing PAM-mutant recognition by AtCas9

The CRISPR-Cas9 system locates genomic targets through gRNA pairing and recognition a protospacer-adjacent motif (PAM). While PAM specificity is typically sequence-determined, we previously found that DNA topology can regulate PAM specificity, relaxing PAMs of various Cas9 effectors and allowing near-PAMless cleavage activity of a type II-C Alicyclobacillus tengchongensis Cas9 (AtCas9). However, the structural mechanism underlying this regulation remains unknown. Here, we report cryo-EM structures of AtCas9 bound to B-form DNA or a 340-bp underwound minicircle DNA bearing WT or mutant PAMs. Despite differences in PAM sequences, all three underwound complexes adopt an almost identical architecture that is distinct from the B-form DNA-bound state. On B-form DNA, AtCas9 recognizes the PAM via base-specific hydrogen bonds and steric exclusion, conferring preference for N4CNNN and N4RNNA (R = A/G). In contrast, underwound minicircle DNA widens the PAM major groove, reduces steric clashes, and enables a compensatory mode involving sequence-independent backbone contacts, explaining near-PAMless cleavage under underwound conformation. These findings uncover a topology-dependent mechanism of PAM recognition and establish a cryo-EM platform using underwound minicircle DNA for structural studies under native-like topological states.

biochemistry↗

bioRxiv2026

Pannexin 2 restrains ER stress-induced Ca2+ dysregulation and inflammatory cardiomyocyte death

BackgroundEndoplasmic reticulum (ER) stress and ER-mitochondria Ca2+ dysregulation contribute to cardiomyocyte injury, yet endogenous regulators at ER-mitochondria interfaces that restrain this cascade remain poorly defined. Pannexin 2 (Panx2), the most structurally divergent pannexin isoform, has been implicated in stress response, but its cardiac localization and function are unclear. MethodsPanx2 localization and function were assessed in human AC16 cardiomyocytes using high-resolution confocal imaging and complementary loss- and gain-of-function approaches during thapsigargin-induced ER stress, with validation in adult mouse ventricular cardiomyocytes. ResultsPanx2 localizes predominantly to the ER and mitochondria-associated membranes, rather than the plasma membrane. Panx2 knockdown reduced ER Ca2+ stores and increased basal cytosolic and mitochondrial Ca2+. During ER stress, Panx2 deficiency markedly amplified Ca2+ dysregulation, mitochondrial dysfunction, unfolded protein response activation, and cytotoxicity, with PERK-dominant signaling and increased IRE1a activation. Notably, PERK inhibition preferentially rescued the Panx2-deficient phenotype, providing the greatest improvement in viability and reduction in cytotoxicity. Panx2 deficiency also enhanced inflammasome/ pyroptotic signaling via the NLRP3-caspase-1-gasdermin D axis. Conversely, Panx2 overexpression suppressed PERK activation and attenuated ER stress-induced injury. Panx2 ablation similarly sensitizes adult ventricular cardiomyocytes to ER stress. ConclusionsPanx2 functions as an organelle-associated checkpoint at ER-mitochondria interfaces that stabilizes Ca2+ homeostasis and limits PERK-dominant ER stress signaling and inflammatory cell death programs in cardiomyocytes, providing a mechanistic framework for cardiomyocyte loss in cardiac disease. Research PerspectiveO_ST_ABS1. What New Question Does This Study Raise?C_ST_ABSDoes Panx2 serve as an endogenous "stress threshold" determinant in cardiomyocytes in vivo, governing when ER stress transitions from adaptive signaling to PERK-driven mitochondrial failure and inflammasome-associated inflammatory cell death during cardiac injury (e.g., ischemia-reperfusion, pressure overload, or cardiometabolic stress)? 2. What Question Should Be Addressed Next?In clinically relevant models of heart disease (ischemia-reperfusion), test whether cardiomyocyte-specific Panx2 loss or augmentation alters infarct size, arrhythmia burden, ventricular remodeling, and functional recovery, and determine whether targeting the Panx2-PERK axis (e.g., selective PERK modulation in the acute reperfusion window or Panx2-directed strategies) reduces cardiomyocyte loss without impairing adaptive stress signaling needed for repair.

cell biology↗