Biology subjects

Bai, Y.

Publications and source records attributed to Bai, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Brain pericytes are an oxidative stress-sensitive cell population damaged through ROS-1 dependent TRPA1 activation.

Oxidative stress is a pathological process driven by an imbalance between the production and clearance of reactive oxygen species (ROS). It is a hallmark of numerous brain disorders, driving neuroinflammation, blood-brain barrier (BBB) disruption, and neurodegeneration. Here, we used two-photon microscopy in rodent brain slices to evaluate cell-type vulnerability to oxidative stress. We identified a microvascular cell population displaying pronounced sensitivity to H2O2 and thiol oxidation. These Pdgfr-{beta} expressing cells were identified as pericytes and perivascular fibroblasts. Because pericytes regulate capillary perfusion and BBB integrity, we examined mechanisms driving their injury. Pericyte damage was independent of apoptosis or necroptosis, but required Ca2+ influx. While blocking voltage-gated Ca2+, TRPC, Orai channels was ineffective, inhibitors of TRPA1 channels reduced pericyte damage. Immunostaining and western blotting showed TRPA1 associated with brain capillaries and pericytes. Functionally, TRPA1 regulated uptake of the pericyte-selective marker NeuroTrace, whereas pericyte GCaMP6f imaging demonstrated that TRPA1 was not the primary driver of cytosolic Ca2+ elevations during oxidative stress. These findings establish pericytes as vulnerable targets of oxidative stress and implicate TRPA1 as a mediator of pericyte structural degeneration. This sensitivity to oxidative stress, mediated by ROS-TRPA1 coupling, could contribute to the pericyte stress and degeneration observed in brain pathology.

neuroscience↗

bioRxiv2026

Deciphering Spatial Cellular Organization through RNA-Anchored Multi-Omics Deconvolution

Spatial technologies that jointly profile RNA and additional molecular layers provide a comprehensive view of tissue organization, yet their limited resolution results in measurements that reflect mixtures of multiple cell types. While RNA-based deconvolution methods are well established, incorporating co-profiled non-transcriptomic modalities without compromising cell-type identifiability remains an open challenge, as reliable references are largely restricted to transcriptomic data. Here we present SMODER, an RNA-anchored framework for spatial multi-omics deconvolution that treats transcriptomes as the primary determinant of cell identity while incorporating complementary molecular modalities in a constrained manner. By adopting an asymmetric integration strategy, SMODER preserves RNA-driven cell-type resolution and enables robust estimation of cell-type compositions across spatial locations. Across simulations and diverse spatial multi-omics datasets spanning protein, chromatin accessibility and histone modification assays, SMODER consistently outperforms existing methods in both accuracy and spatial coherence. Beyond deconvolution, SMODER denoises multi-omic signals and enables cell-type-aware analysis of regulatory programs. Application to spatial CUT\&Tag--RNA-seq and {RNA--ATAC-seq} data reveals spatially resolved epigenetic repression and cis-regulatory relationships linked to gene expression.

bioinformatics↗

bioRxiv2026

A split-control criterion for few-shot adaptation in single-cell perturbation prediction

Few-shot adaptation can help or harm single-cell perturbation prediction, but conventional evaluation shares a control estimate between calibration responses and held-out targets. We show how methods carry control error into their predictions and derive its contribution to score inflation. Nested control-depth experiments support inverse-depth scaling of inner-product inflation; correlation inflation also depends on the control noise-to-signal ratio. Independent-control scoring changed the rank of 40 of 52 configuration-dataset entries. We introduce SafeDelta, a split-control criterion that uses calibration data to decide whether to adapt. Across six datasets, mean gated gain was non-negative under the original two-control evaluation. On a deep plate, fixed predictions and decisions retained positive mean gains under three additional independent control references. The same reproducibility principle identified a fibrosis programme that localises to scar in human liver. These results inform adaptation decisions and control-depth planning.

bioinformatics↗

bioRxiv2026

FLASH X-rays preserve neutrophil chromatin to boost antitumor immunity

Ultrahigh dose-rate FLASH radiotherapy spares normal tissue while preserving antitumor activity, positioning it as a promising technology in radiation oncology, but its immunomodulatory mechanisms remain elusive. Here, using a bilateral subcutaneous tumor model in mice, we show that 8-Gy FLASH X-rays, versus an equal dose of conventional dose-rate (CONV) X-rays, elicit a robust abscopal antitumor effect with anti-PD-1 therapy. Single-cell transcriptome and T cell receptor (TCR) profiling reveal that FLASH X-rays plus anti-PD-1 enhance antitumor immune infiltration and TCR clonal expansion in both irradiated and abscopal tumor lesions. Mechanistically, the ultrashort temporal continuity of FLASH dose delivery conserves chromatin compaction in neutrophils during exposure and inhibits neutrophil extracellular trap (NET) formation, thereby dismantling NET-mediated CD8+ T-cell exclusion within primary tumors. Conversely, CONV or split-dose FLASH X-rays induce marked chromatin modifications prior to dose completion, leading to chromatin hyper-relaxation which promotes NETosis and consequently abrogates systemic antitumor immunity. Notably, this detrimental effect can be reversed by pharmacologically suppressing PARylation-mediated chromatin modification and decondensation in neutrophils. These findings identify radiation-induced aberrant chromatin relaxation in neutrophils as a critical determinant of radioimmunotherapy outcomes, providing a rationale for redefining the FLASH effect and advancing its clinical translation.

cancer biology↗

bioRxiv2026

Systemic control and inter-organ communication of ovarian aging

Whether ovarian aging is intrinsic and unidirectional or dynamically regulated by systemic context remains an open question for fertility and women's healthspan. To address it, we developed a mouse ovarian transcriptomic aging clock (OvaAge) and applied it, together with published transcriptomic, epigenetic and pathway-resolved DNA methylation (PathAge) clocks, multi-omic analyses and reproductive outcomes, to new reciprocal heterochronic ovary transplantation and parabiosis experiments. Ovarian molecular age shifted in both directions: aged ovaries became younger in young hosts and young ovaries became older in aged hosts, and in each case the shift was partial across transcriptomic, epigenetic and pathway-resolved measures. Ovaries from 13-month-old C57BL/6J donors supported full-term pregnancies and live births at 17-18 months of age when transplanted into young hosts, but not when transplanted into old hosts, and young ovaries supported live births in 17-18-month-old recipients. Donor ovary age altered the transcriptomic age of the uterus in both directions, while young ovaries also lowered the transcriptomic age of aged liver and brain, identifying the ovary as an active node within an inter-organ aging network. Across unilateral and bilateral transplantation and parabiosis, an older environment increased inflammatory gene expression in the ovary, whereas a younger environment reduced it and increased mitochondrial and biosynthetic programs. Integration of methylation, expression and cell-type markers linked these changes to declining oocyte-associated programs and an expanding stromal compartment enriched for multinucleated giant cells (MNGCs). MNGC-rich regions formed a reversibly remodeled, focally aged niche with distinct spatial metabolic features, and a related macrophage expression signature was detected in human ovaries. Together, these findings identify ovarian aging as a modular, bidirectionally plastic process that is regulated by the systemic environment and point to tractable intervention points.

systems biology↗

bioRxiv2026

A 21-Color Spectral Flow Cytometry Panel for Comprehensive Immunophenotyping of Rat Tissues and a Companion 9-Color T-Cell Functional Assay

Although rats are crucial translational research models due to their immunological homology and surgical feasibility, the scarcity of conjugated antibodies has hampered high-dimensional immune profiling. To bridge this gap, we created a synergistic two-panel method that uses full-spectral flow cytometry: a 21-color comprehensive immunophenotyping panel and a 9-color intracellular cytokine staining (ICS) panel. The 21-color panel navigates the limited fluorophore pool and maps innate and adaptive lineages at high resolution. While it can be used to profile neutrophils and monocytes in peripheral blood it reaches its full potential in lymphoid organs, allowing for the simultaneous evaluation of tissue-resident macrophages, dendritic cells, T cell differentiation (including Tregs), and APC function. Based on this phenotypic paradigm, the 9-color ICS panel dissects effector T cell activation and Th1/Th2/Th17 cytokine production. Furthermore, we reserved the PE color during panel creation, allowing for the use of antibodies and probes with PE or comparable fluorophores in conjunction with this panel, hence increasing overall flexibility. This combination technique, designed for rat peripheral blood, spleen, and lymph nodes, combines panoramic phenotyping with functional analysis, offering an adaptable foundation for complicated tissue microenvironments in tumor immunology, rheumatology, and autoimmunity research.

immunology↗

bioRxiv2026

The cleaved C-terminal domain of GmERS1-1 modulates cell cycle via GmACR1

Ethylene signaling orchestrates plant development and stress adaptation, yet how post-translational modifications of its receptors coordinate growth regulation remains unresolved. Here, we uncover a proteolytic processing mechanism of the soybean ethylene receptor GmERS1-1 that directly gates cell cycle progression. The GmERS1-1 mutants exhibit elevated yield under field conditions, whereas overexpression suppresses growth and hypersensitizes plants to ethylene. Ethylene triggers nuclear translocation of C-terminal domain (GmERS1-1-CEND), which is indispensable for receptor function. Mechanistically, GmERS1-1-CEND scaffolds a trimeric complex with GmACR1 and GmCDK7, enforcing G2/M phase arrest, thereby decoupling cell division from canonical ethylene transcriptional responses. Strikingly, ethylene-induced cell cycle blockade during apple fruit maturation mirrors this pathway, suggesting deep conservation across angiosperms. Our work defines a receptor processing-dependent signaling axis that directly interlinks phytohormone perception with cell cycle control, proposing tunable targets (e.g., GmERS1-1 cleavage efficiency) for engineering crop architecture and productivity.

plant biology↗

bioRxiv2026

Long-form hibernation-promoting factor coordinates 100S assembly and translational repression

Ribosome hibernation mediated by long-form hibernation-promoting factor (HPF) requires coordination of ribosome dimerization and translational repression, but how these functions are integrated remains unclear. Here, we present cryo-EM structures of native 100S from a deep-sea Bacillus isolate, revealing a conformationally heterogeneous 100S population. Beyond the established roles of the HPF N-terminal domain (NTD) in decoding-center occlusion and the C-terminal domain (CTD) in dimerization, our analyses reveal additional contributions from the Linker and a charged CTD surface near the 16S rRNA 3' terminus containing the anti-Shine-Dalgarno (aSD) sequence. Linker substitutions differentially affect translational repression while retaining 100S formation, with distinct effects of the two Linker segments. Mutation of the charged CTD surface enhances translational repression while retaining robust 100S formation, suggesting an additional role beyond CTD-mediated ribosome dimerization. Functional analyses in an E. coli cell-free translation system further show that the inhibitory activity of individual HPF regions varies with translational context. Together, these findings support a modular model in which the NTD, Linker, and CTD make distinct but interconnected contributions to 100S assembly and translational repression.

biochemistry↗

bioRxiv2026

Stressed alga-free coral cells can initiate coral bleaching

Coral bleaching is driving the rapid decline of coral reefs worldwide, yet a fundamental question remains unresolved: does the bleaching cascade begin in the coral host or in its intracellular algal symbionts, Symbiodiniaceae? Resolving where this process starts is critical for understanding how symbiosis collapses and where early intervention might be effective. Here we use transient stress to create a temporal window between the early cellular response and subsequent symbiosis breakdown. Across transient menthol and thermal stress in soft and stony corals, bleaching developed after the stress had ended. In Xenia sp., single-cell transcriptomics revealed a broad host response before detectable symbiont loss, including coordinated redox changes consistent with conditions favouring reactive oxygen species (ROS) accumulation. Cell-resolved imaging showed that alga-free coral cells were the first to become ROS-positive, whereas Symbiodiniaceae showed no detectable ROS signal. This early host response was transmissible. Conditioned medium from stressed cultures induced the emergence of ROS-positive host cells and subsequent symbiosis breakdown in unstressed recipients. Purified ROS-positive alga-free coral cells alone were sufficient to trigger symbiosis breakdown in recipient cultures without direct stress exposure. Suppressing the early emergence of ROS-positive coral cells markedly reduced later bleaching, whereas intervention after stress was substantially less effective. These findings identify a host-initiated, intercellularly propagating route to coral bleaching and reveal an early host response that can determine the subsequent fate of the symbiosis.

cell biology↗

bioRxiv2026

Intranasal adenovirus type 5 influenza vaccination enhances milk antibody responses and passive transfer to neonatal ferrets

Newborns and infants are particularly vulnerable to influenza, largely due to the immaturity of their immune systems. As such, maternal immunization is a valuable strategy to enhance influenza-neutralizing antibodies in both blood and breast milk, ensuring optimal passive immunity transfer to the infant. In our pregnant and lactating ferret maternal-neonatal model, we evaluated antibody responses to an adenovirus type 5-vectored H1N1 hemagglutinin vaccine delivered enterically, intranasally, or intramuscularly. While all three routes elicited a robust antibody response compared to saline-treated controls, intranasal vaccination significantly increased influenza-specific antibodies in dam serum, upper respiratory tract secretions, and milk, and subsequent transfer to suckling kits. Our results suggest that intranasal immunization was the most effective route for inducing functional influenza-specific antibodies in both dam serum and milk, with efficient passive transfer to suckling kits. Leveraging mucosal immune induction may enhance maternal antibody responses, transfer to offspring, and downstream neonatal protection.

microbiology↗

bioRxiv2026

A patient-centric therapeutic paradigm uncouples prostate cancer suppression from systemic metabolic collapse

The clinical benefits of cancer therapies are often compromised by the tolerable adverse effects that impair systemic organismal health and may evolve into latent life threats. Here, we identified profound abiraterone-induced but androgen-independent metabolic perturbations in prostate cancer patients and developed Lifehug-9892 to balance tumor therapy with systemic metabolic homeostasis. By integrating population cohorts with high-resolution metabolomics, we demonstrate that abiraterone induces profound systemic lipidomic dysregulation, characterized by the massive, pathological accumulation of desmosterol. Abiraterone inhibits but stabilizes DHCR24, leading to a metabolic trap in patients showing elevated levels of both desmosterol and cholesterol. Desmosterol accumulation is highly lipotoxic, potently triggering endothelial cell senescence and necrosis, macrophage foam cell formation, murine atherosclerosis, and hepatic senescence. To mechanistically uncouple and therapeutically rescue this systemic metabolic collapse, Lifehug-9892 was rationally designed to selectively retain on-target CYP17A1 inhibition while completely sparing DHCR24 function. Lifehug-9892 maintains potent tumor-suppressive activity while fully preserving the desmosterol-cholesterol metabolic axis and preventing systemic cardiovascular and hepatic damage. Our study uncovers a critical mechanistic link between drug-induced metabolic dysregulation and organismal health in cancer patients, providing a biochemical framework for developing patient-centric targeted therapies that preserve host homeostasis.

cancer biology↗

bioRxiv2026

Patterns and environmental drivers of amphibian alpha and beta diversity in the Huangshan Mountains, southern Anhui, China

Understanding the spatial patterns of biodiversity and their environmental determinants is fundamental to ecology and conservation, particularly in mountainous transitional zones where species assemblages can shift rapidly. Amphibians, as highly sensitive organisms, are excellent indicators of environmental change, yet quantitative assessments of their diversity in the Huangshan Mountains-a biodiversity hotspot at the junction of the Palaearctic and Oriental realms in southern Anhui, China-remain limited. We conducted systematic line-transect surveys across 200 grids (5 km x 5 km) during the spring and autumn of 2023 and 2024, recording a total of 10,342 individuals belonging to 23 species, 20 genera, 9 families, and 2 orders. Three species (Fejervarya multistriata, Microhyla fissipes, and Bufo gargarizans) were identified as dominant, and two nationally protected species (Hoplobatrachus chinensis and Andrias davidianus) were detected. Inter-annual alpha diversity did not differ significantly, but pronounced seasonal variation was observed, with spring supporting higher Shannon-Wiener and Pielou evenness than autumn in both years. Using generalized additive models and model averaging, we found that annual precipitation and the normalized difference vegetation index (NDVI) were consistently the strongest positive predictors of Shannon-Wiener diversity, Simpson dominance, and species richness, while species richness also declined significantly with increasing human footprint. Total beta diversity (Soerensen dissimilarity) was very high (0.981) and overwhelmingly driven by species turnover (97.86%) rather than nestedness. Partial Mantel tests and distance-based redundancy analysis further revealed that environmental distances-particularly annual precipitation-significantly shaped overall beta diversity and its turnover component after accounting for geographic distance. These results highlight the predominant role of climatic and vegetation gradients in structuring amphibian assemblages in this subtropical mountainous region, providing baseline data to inform local conservation strategies.

ecology↗

bioRxiv2026

Probiotic-Directed Fermentation Reprograms the Metabolic Profile of a Traditional Mongolian Whole-Wheat Diet and Modulates Escherichia coli-Induced Gut Microbiota Dysbiosis

Traditional Mongolian fermented foods have been extensively utilized for dietary regulation and the promotion of gastrointestinal health. However, spontaneous fermentation remains inherently unpredictable, leading to significant variations in microbial community dynamics, metabolite accumulation, and the consistency and quality of the final product. Drawing on the traditional preparation of Mongolian acidic foods, this study established a controlled production strategy for whole-wheat probiotic fermented soup (WWPFS) by combining enzymatic pretreatment with probiotic-directed fermentation. Physicochemical characterization, 16S rRNA gene-based microbial community profiling, LC-MS/MS-based untargeted metabolomics, safety evaluation, and an Escherichia coli-induced gut microbiota dysbiosis model were employed to optimize and comprehensively characterize the fermentation process of WWPFS. The optimized process established a reproducible fermentation system consistently dominated by Lactobacillus and Bacillus across independent fermentation batches. Compared with traditional spontaneous fermentation, probiotic-directed fermentation remodeled the physicochemical properties of the whole-wheat matrix, including carbon, nitrogen, phosphorus, sulfur, and mineral composition, and facilitated the accumulation of putatively annotated LC-MS/MS features, including DL-lactate, 1,4-D-xylobiose, diacetyl, and phenyllactic-acid-related features derivatives. Acute oral and 28-day repeated-dose toxicity evaluations showed no treatment-related adverse effects within the tested dose range and study duration. In the Escherichia coli-induced gut microbiota dysbiosis mouse model, microbial richness, diversity, and community structure differed among the experimental groups, and both low- and high-dose WWPFS groups showed significant shifts in overall gut microbial community composition relative to the model group after multiple-testing correction, together with directional recovery of selected model-responsive bacterial genera. Cross-system integration identified coordinated response patterns between fermentation-derived metabolite features and model-responsive gut bacterial taxa, supporting a potential metabolite-microbiota link in WWPFS-mediated gut microbiota modulation. In summary, probiotic-directed fermentation improved the controllability of the traditional Mongolian fermented food production process, reshaped its metabolic profile, and enhanced its potential to modulate the gut microbiota. These findings provide experimental evidence supporting the modernization of traditional Mongolian fermented foods and the development of probiotic-based functional foods.

microbiology↗

bioRxiv2026

Coevolution-driven reconstruction of multi-taxa siderophore interaction networks reveals topological diversity of microbial exploitation

Microbial communities are shaped by secreted metabolites that mediate ecological interactions, yet predicting these interactions from genomic sequences remains difficult, because the specific recognition between co-functional metabolites (CFMs), such as siderophores, and their receptor proteins (Rec) cannot be inferred from gene annotation alone. This difficulty arises from three factors: the prevalence of Rec-mediated exploitation, the lack of high-accuracy functional annotations, and the absence of genomic co-localization between functionally paired CFM-Rec in Gram-positive bacteria. Here we present the Coevolution-based Interaction Model (CIM), an automated framework that maps specific CFM-Rec pairings directly from uncurated genomic datasets. Using a dynamic joint optimization strategy that accounts for exploitation asymmetry and avoids combinatorial explosion, CIM identifies functional pairings solely through evolutionary covariation. We validated this approach by reconstructing macroscale iron scavenging networks across nine bacterial taxa. Experiments confirmed that CIM can bridge genomic distances exceeding 3 Mb in the Gram-positive genus Rhodococcus to identify unlinked cognate receptors, and can accurately predict cross-utilization by exploiter strains despite substantial receptor sequence heterogeneity in Burkholderiaceae and Rhizobiaceae. Finally, topological analysis of the reconstructed networks shows that siderophore exploitation acts as a universal topological glue, fusing fragmented microbial populations into highly connected communities, and that the exploitability of siderophore production reverses depending on network modularity. CIM thus offers a scalable, sequence-to-ecology approach for predicting interactions mediated by secondary metabolites in microbial communities.

systems biology↗

bioRxiv2026

cf-Cabernet: Nick Repair Prior to End Repair Preserves Endogenous DNA Methylation Information in Cell-Free DNA Methylation Sequencing

Cell-free DNA (cfDNA) methylation profiling holds great promise for non-invasive cancer detection, yet accurate methylome analysis is compromised by DNA damage inherent to cfDNA. Standard library preparation workflows involve an end-repair step during which DNA polymerases can initiate synthesis from single-strand breaks (nicks), replacing endogenous methylated nucleotides with unmethylated nucleotides in the 3' direction and systematically erasing methylation information. This artifact is distinct from the terminal jagged-end effect and disproportionately affects cfDNA and FFPE DNA, which harbor abundant nicks. Here, we developed cf-Cabernet, which builds upon the Cabernet framework (Cao et al., 2023) -- an enzymatic methylation sequencing method featuring carrier DNA-assisted sample recovery and amplification-friendly post-conversion processing -- with the addition of a Taq DNA ligase-mediated nick repair step prior to end repair. Using matched cfDNA samples, we compared cf-Cabernet against standard EM-seq and WGBS. cf-Cabernet and EM-seq both substantially outperformed WGBS in alignment rate. Critically, while standard EM-seq exhibited globally reduced methylation levels compared to WGBS, cf-Cabernet yielded methylation levels concordant with WGBS. M-bias analysis revealed that EM-seq libraries showed persistently depressed methylation across the entire read length, whereas cf-Cabernet methylation recovered to the WGBS baseline beyond the terminal [~]40 bp jagged-end region. Nick-induced methylation erasure during end repair is a significant but previously underappreciated source of error in cfDNA methylation sequencing. cf-Cabernet effectively mitigates this artifact through pre-emptive nick ligation, enabling accurate methylome profiling from damaged DNA templates. This method is broadly applicable to cfDNA, FFPE DNA, and other clinical specimens where DNA integrity is compromised, providing a robust foundation for methylation-based liquid biopsy applications.

genetics↗

bioRxiv2026

Combining prior knowledge and transcriptomics data for logic models of patient subgroups

Computational modeling provides a powerful framework for in silico exploration of anti-cancer therapeutic targets and tumor response mechanisms. Oncogenic signaling pathways play a central role in tumor behavior and represent promising targets for personalized combination therapies. However, these pathways are complex, and although logic-based models are well suited for representing signaling dynamics, they are often constrained by model-specific data requirements, limited scalability, and time-consuming manual curation. Here, we introduce Functional Integration of Contextualized Omics for Unraveling regulatory dynamicS (FICUS), a framework that integrates omics-driven network contextualization with dynamic Boolean and logic-ODE modeling. FICUS enables automated, data-driven protein network inference and patient stratification, allowing shared signaling mechanisms to be identified across patient subgroups while preserving patient-specific dynamic responses. We applied FICUS to the SU2C-MARK lung cancer cohort and the The Cancer Genome Atlas kidney cancer cohort, demonstrating its utility for post-hoc analyses and downstream interrogation of dynamic tumor models. Overall, our results highlight the flexibility of FICUS in capturing heterogeneous signaling mechanisms across patient subgroups, addressing a key challenge in precision oncology.

Systems Biology↗

bioRxiv2026

A recombinant dilp2GS-rpr donor line for adult-inducible IPC ablation across Drosophila genetic backgrounds

Genetic-background studies require defined perturbations that can be crossed reproducibly into many recipient backgrounds. We generated a Drosophila dilp2GS-rpr donor line for adult-inducible ablation of insulin-producing cells (IPCs), which secrete insulin-like peptides and provide a tractable model of insulin-deficient metabolic physiology. This line carries dilp2-GeneSwitch-GAL4 and UAS-reaper in cis on the same second chromosome homolog over a balancer. PCR genotyping and sequencing confirmed both transgenic elements in the candidate recombinant line. RU486 induction reduced dilp2 mRNA expression, supporting partial IPC ablation. Treatment-duration testing identified 8 days of RU486 as sufficient to increase whole-body glucose in the dilp2GS-rpr line but not in the background-matched control; food intake did not differ between RU486- and vehicle-treated flies. Across metabolic assays, whole-body glucose showed the clearest RU486- and line-dependent phenotype. This validated dilp2GS-rpr line enables testing how recipient genetic backgrounds modify inducible IPC/DILP metabolic phenotypes and provides a framework for similar linked donor-line resources.

genetics↗

bioRxiv2026

OmniPath Metabo: chemical structures, interactions and mechanisms to study the metabolome

Mechanistic and functional analysis of omics data largely relies on the incorporation of prior knowledge; however, connecting metabolomics data and knowledge is a major methodological challenge. This is largely driven by the diverse prior knowledge being fragmented across many databases requiring the merging of different database records across chemical structures, identifiers, and varying levels of structural specificity. Hence, this limits mechanistic interpretation and functional characterisation of the metabolome. Here, we present OmniPath Metabo, a comprehensive, harmonized, metabolome-centric database covering metabolites, lipids, food-derived compounds, and small molecule drugs, along with their associated receptors, transporters, enzymes, reactions, allosteric regulators, and disease associations. OmniPath Metabo harmonizes attributes using controlled vocabularies and ontologies, structures and built-in cheminformatics to map identifiers and track ambiguity. OmniPath Metabo is built directly from 40+ original resources and is freely accessible via an interactive web app and API at metabo.omnipathdb.org. OmniPath Metabo enables dynamic, context-specific construction of subnetworks to serve dedicated purposes, such as cell-cell communication or integrated multi-omics metabolite-driven regulation, connecting reactions, allosteric regulation, metabolite-receptor and metabolite-transporter interactions. Combining it with the over 170 other resources in OmniPath, it can be used for integrated networks of signaling, gene regulation, and metabolism. We showcase the application of OmniPath Metabo by analysing publicly available metabolomics data of lung cancer cell lines and metabolic footprints to mutational patterns. In summary, OmniPath Metabo transforms fragmented resources into a harmonised prior knowledge framework for a mechanistic and functional analysis of the metabolome.

bioinformatics↗