Biology subjects

Zhao, P.

Publications and source records attributed to Zhao, P..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

LATTE for locus-specific quantification of transposable element expression across species

Transposable elements (TEs) are pivotal drivers of eukaryotic genome evolution and phenotypic diversity. However, their functional contributions to complex traits remain largely obscured by expression quantification challenges arising from high sequence homology and multi-mapping ambiguities. Here, we present LATTE, an efficient computational framework for defining and quantifying TE expression at locus-specific resolution by leveraging an innovative multi-indicator Expectation-Maximization (EM) algorithm. Extensive benchmarking against simulated datasets demonstrated that LATTE significantly outperformed existing state-of-the-art tools, achieving an accuracy of 0.998 at the subfamily level and 0.839 at the locus-specific level. Applying LATTE to 813 RNA-seq datasets across humans, cattle, and chickens, we quantified expression profiles of 2,703 TEs, followed by TE-expression quantitative trait loci (TE-eQTL) mapping. The colocalization rates between TE-eQTL and host gene-eQTL was low, revealing a distinct regulatory landscape of TE expression. This decoupled correlation between TEs and host genes are likely mediated by the differential expression of alternative transcripts. Through integrated TE-eQTL and genome-wide association studies on 3,746 complex traits across three species, we demonstrated that TEs constitute 204 (8.7%) additional associations with complex traits beyond gene-eQTL. More specifically, the Sjogrens syndrome-associated variant rs10954213 acts as a TE-eQTL that shifts the splicing landscape of IRF5, upregulating TE-containing transcripts while simultaneously suppressing canonical ones. Collectively, LATTE provides an efficient framework for studying TE expression across species, and our findings highlight the key role of TEs in understanding the genetic architecture of complex phenotypes.

bioinformatics↗

bioRxiv2026

The enhanced multi-tissue atlas of regulatory effects in cattle

Cattle are integral to global food security, yet the molecular architecture of their complex traits remains poorly understood. Here, we present the Cattle Genotype-Tissue Expression (CattleGTEx) Phase 1 resource (https://cattlegtex.farmgtex.org/), a substantial expansion of the pilot study. By leveraging 12,422 RNA-seq profiles across 43 tissues and 82 breeds, we characterized 433,972 primary and 161,428 non-primary regulatory effects spanning seven molecular phenotypes. This high-resolution atlas resolves 75% of GWAS signals for 44 complex traits, significantly addressing the "missing regulation" in livestock. We propose a genetic regulatory model demonstrating how variants across multiple biological layers interact with specific biological contexts to shape phenotypic variation. Furthermore, CattleGTEx elucidates mechanisms underlying adaptive evolution between Bos taurus and Bos indicus, as well as artificial selection in dairy and beef breeds. Finally, by mapping evolutionary constraints on these regulatory effects, we demonstrate the translational value of this resource for prioritizing causal variants in human complex diseases. Together, Phase 1 of CattleGTEx provides a transformative framework for functional genomics, precision breeding, and comparative genetics.

genetics↗

bioRxiv2026

Sex-specific Genetic Regulatory Effects in Chickens

Sexual dimorphism is a defining vertebrate feature, yet its sex-specific molecular architecture remains poorly understood. Here we established a sex-balanced, uniformly reared chicken cohort to map this landscape, integrating individual whole-genome sequencing with 7,969 bulk and 779,380 single nucleus transcriptomes across 32 tissues from 280 birds. We identified 495,098 independent expression quantitative trait loci for 20,194 genes, including 10,937 loci modulated by cell-type composition. Notably, 340 genes were regulated by 449 loci in a sex-dependent manner, significantly enrichment in endocrine tissues like adipose and the adrenal gland. Furthermore, we fine-mapped 1,219 structural variants, demonstrating their unique roles to tissue- and sex-specific expression beyond SNPs. Ultimately, we showed the utility of these regulatory effects in elucidating the molecular basis of metabolism and complex traits in both chickens and humans. This comprehensive atlas of regulatory effects provides profound insights into the genomic and molecular basis of sexual dimorphism in vertebrates.

genomics↗

bioRxiv2026

Exploring the Influence of Chemical Exposures in Breast Cancer Disparities: High-Throughput Transcriptomic Analysis in Normal Breast Cells from Diverse Donors

Racial disparities in the incidence of, and mortality from, aggressive breast cancers are a pressing public health issue. Many factors have been investigated in these inequities; however, the role of toxicant exposures is not well characterized. We and others have identified substantial inequities in chemical biomarker concentrations by race. The goal of this study was to test the hypothesis that exposure to these chemicals is linked to biological changes relevant to aggressive breast cancers, such as dysregulation of the Hallmarks of Cancer. We used high throughput transcriptomic profiling of normal primary human breast epithelial cells from diverse donors (n=6) to test effects of 8 chemicals (cadmium, lead, arsenic, copper, PFNA, BPA, BPS, p,p-DDE) with documented exposure disparities by race/ethnicity across 3 concentrations (100nM, 1{micro}M, 10{micro}M). Across chemicals, we identified that pathways related to cell cycle regulation and protein secretion were commonly affected. Through bioinformatic estimation of cell type proportions, we found that metals like lead and cadmium induced cell-type shifts, consistent with the dysregulated cellular plasticity cancer hallmark. Lead and arsenic response genes were enriched for genes associated with poor breast cancer survival in the Cancer Genome Atlas. Integrating concentration-response modeling and chemical biomonitoring data, BPA, p,p-DDE, copper, and lead elicited expression changes at concentrations relevant to the US population. Finally, we identified substantial interindividual heterogeneity in response to organic compounds, but less so in metals. These findings highlight the value of high-throughput transcriptomics as a New Approach Methodology (NAM) in quantifying how common exposures may impact aggressive breast cancer associated biological processes.

pharmacology and toxicology↗

bioRxiv2026

A non-canonical EZH2/TRIM28 epigenetic axis drives heparan sulfate remodeling and melanoma metastasis

Melanoma progression and metastasis are driven not only by oncogenic alterations but also by epigenetic programs that dynamically remodel the tumor microenvironment. Heparan sulfate (HS) proteoglycans are key extracellular matrix components that integrate growth factor signaling, cell-matrix interactions, and migratory behavior by controlling ligand availability and receptor engagement, yet how chromatin-associated factors regulate HS remodeling in cancer remains poorly defined. Here, we identify the histone methyltransferase EZH2 as a key regulator of HS biosynthesis in melanoma. Integrated bioinformatic and genomic analyses revealed enrichment of EZH2 and additional Polycomb Repressive Complex (PRC) factors at regulatory regions of HS biosynthetic genes. CRISPR-mediated loss of EZH2 altered expression of multiple HS-modifying enzymes, most notably the secreted endosulfatases SULF1 and SULF2, resulting in enhanced HS 6-O sulfation and altered ligand binding at the cell surface. Unexpectedly, EZH2 promoted SULF1 expression through a methyltransferase-independent mechanism via a non-canonical interaction with TRIM28, whereas SULF2 was regulated through canonical PRC2-mediated repression. Functionally, SULF1 depletion impaired melanoma cell migration and invasion in vitro and reduced spontaneous metastasis in an orthotopic xenograft model. Together, these findings define an epigenetic axis linking chromatin regulation to extracellular glycan remodeling and identify HS-modifying enzymes as candidate targets to limit melanoma metastasis.

molecular biology↗

bioRxiv2026

Spatiotemporal Mapping of Tertiary Lymphoid Structure Heterogeneity Shapes Immune Niches and Clinical Outcomes in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy with limited therapeutic options. The spatial architecture and functional diversity of tertiary lymphoid structures (TLSs) in iCCA remain unclear. Here, we present a multimodal spatial atlas of TLSs and identified Intra-tumoral TLSs (iTLSs) as independent prognostic markers. Bulk proteomic profiling of 214 discovery and 155 validation cases identified a four-tier TLS-based TME classification system and supported development of a TLS-predictive random forest classifier. Imaging mass cytometry revealed that iTLS tumors harbor structured immune architectures, where M1-like tissue-resident macrophages (RTMs), dendritic cells, and CXCL13 CD4 T cells co-localize to form antigen-presenting neighborhoods (apc-CNs) spatially coupled to TLS core regions (TLScore-CNs). Single-cell spatial transcriptomics further resolved 61 TLSs into 14 spatial niches and defined a pseudo-temporal maturation continuum: aggregated, activated, and post-activated. Intra-niche communication, primarily mediated by ifnCAFs, iCAFs, and CXCL12 macrophages, evolved dynamically with maturation. Single-nucleus RNA-sequencing combined with Tangram-based spatial mapping revealed CXCL12 macrophages and iCAFs forming a peripheral band in aggregated TLSs, while ifnCAFs infiltrated TLS interiors during activation. These findings define TLS heterogeneity and provide insights for stroma-directed immunotherapy. TeaserAn atlas of tertiary lymphoid structures reveals immune-stroma interactions in Intrahepatic cholangiocarcinoma.

immunology↗

bioRxiv2025

The conserved NUS-1/DHDDS complex links N-glycosylation to lipid and lysosomal homeostasis in C. elegans

N-glycosylation, driven by the cis-prenyltransferase (cis-PT) complex, a NUS1 and DHDDS heterotetramer, is vital for proteome integrity. Despite being linked to severe congenital disorders of glycosylation (CDGs), the systemic role of NUS1/DHDDS remains elusive. Here, we characterize the conserved C. elegans cis-PT complex and uncover a critical crosstalk with global lipid metabolism. cis-PT deficiency induces catastrophic ER stress, global glycoprotein defects, and developmental failure. Mechanistically, NUS-1 physically interacts with the core oligosaccharyltransferase (OST) complex, directly coupling substrate synthesis to N-glycan transfer. Loss of NUS-1 or DHDDS causes systemic lipopenia, lysosomal dysfunction, and cholesterol sequestration, resulting from impaired N-glycosylation of key regulatory glycoproteins like SCAP. Utilizing CDG-associated CRISPR models, we resolve the molecular basis for cis-PT dysfunction, identifying interface disruption and catalytic impairment as distinct disease etiologies. These findings collectively reveal a critical and previously unappreciated crosstalk between protein glycosylation and global lipid metabolism, establishing a robust system to explore CDG pathology and therapeutic strategies.

cell biology↗

bioRxiv2025

Mucin-type O-glycans regulate proteoglycan stability and chondrocyte maturation

O-glycosylation is a ubiquitous post-translational modification essential for protein stability, cell signaling, and tissue organization, yet how distinct O-glycan subclasses coordinate tissue development remains unclear. Here, we identify functional crosstalk between extended mucin-type O-glycans and heparan sulfate proteoglycans (HSPGs). Genetic ablation of {beta}-1,3-galactosyltransferase 1 (C1GALT1) or its chaperone COSMC in human chondrocytes reduced cell surface HSPGs and fibroblast growth factor (FGF) binding, leading to impaired MAPK/ERK signaling, which was recapitulated in hypomorphic COSMC-CDG patient cells. Transcriptomic and secretome analyses revealed selective loss of proteoglycan expression and broader extracellular matrix remodeling in COSMC- and C1GALT1-deficient cells. Mechanistically, truncation of O-GalNAc glycans reduced Syndecan-1 levels at the cell surface via enhancing its lysosome-dependent degradation and diminished CD44v3-mediated FGF1 binding. Functionally, loss of complex O-GalNAc glycans disrupted chondrogenesis of growth plate-like chondroprogenitors. Overall, these findings reveal previously unrecognized roles for mucin-type O-glycans in maintaining proteoglycan stability and function, highlighting cross-regulatory mechanisms of glycosylation crucial for normal development that likely contribute to the pathophysiology of glycosylation-related disorders.

cell biology↗

bioRxiv2025

3D Hybrid Bioprinting for Complex Multi-Tissue Engineering

3D bioprinting has revolutionized tissue engineering, enabling intricate, physiologically relevant constructs unattainable with conventional techniques, yet it remains limited in integrating soft and rigid multifunctional components for complex multi-tissue applications. In this study, we introduce a 3D hybrid bioprinting approach implementing the Hybprinter platform, which integrates multiple 3D printing modules under optimized conditions for a continuous bioprinting process with multiple soft and hard biomaterials. This approach demonstrates robust biocompatibility and broad tissue engineering potential for modeling and therapeutic applications. The capacity to fabricate multi-hydrogel hybrid constructs is illustrated by representative examples highlighting vascularization, multifunctionality, mechanical robustness, and implant suturability. Notably, compared with commonly fabricated hydrogel-only constructs, the resulting hybrid constructs achieve over a 1000-fold increase in mechanical strength, and demonstrated enhanced osteogenic differentiation, underscoring their suitability for load-bearing musculoskeletal and orthopedic tissue engineering. Additionally, cell-laden hydrogel constructs demonstrated robust chondrogenic differentiation, highlighting the capacity for lineage-specific tissue development in vitro. Beyond these outcomes, the presented hybrid bioprinting approach integrates essential tissue engineering attributes that unites mechanical robustness and suturable capacity with multi-material integration, gradient property design, incorporation of bioactive agents, and support for multi-cell loading. This versatile platform advances complex tissue engineering and holds promise for patient specific, organ-on-demand applications.

bioengineering↗

bioRxiv2025

A Generative Foundation Model for Antibody Design

Antibodies are indispensable components of the immune system, yet the design of high-affinity antibodies remains a time-consuming and experimentally intensive process. To address this challenge, we present IgGM, a novel generative foundation model designed to accelerate high-affinity antibody engineering. IgGM learns the complex relationships underlying the binding interactions between antigens and antibodies, as well as the mapping between antibody sequences and structures. By conditioning on different inputs, IgGM supports a wide range of antibody design tasks, including complex structure prediction, inverse design, affinity maturation, framework optimization, humanization, and de novo antibody design. It is compatible with both conventional antibodies and nanobodies, and allows user-defined CDR loop lengths for flexible design. To prioritize candidates, we introduce a frequency-based computational screening strategy that enhances design efficiency. Extensive evaluation through both in silico benchmarks and in vitro experiments across diverse antigens such as PD-L1, Protein A, TNF-, IL-33, SARS-CoV-2 RBD and its variants demonstrates that IgGM consistently generates antibodies or nanobodies with high measured affinity. These results underscore IgGMs versatility and effectiveness as a powerful tool for next-generation antibody discovery and optimization.

bioinformatics↗

bioRxiv2025

Rapid elicitation of a new class of neutralizing N332-glycan independent V3-glycan antibodies against HIV-1 in nonhuman primates.

Sequential immunization is a promising approach to elicit broadly neutralizing antibodies (bNAbs) against the HIV-1 Envelope (Env). However, available protocols are inefficient and involve multiple immunizations over long periods of time. Here, we present WIN332, a new engineered Env-immunogen that induces a new class of neutralizing N332-glycan-independent antibodies to the conserved V3-glycan epitope of Env after a single bolus immunization in nonhuman primates. WIN332 binds to precursors of canonical human N332-glycan-dependent (Type-I) V3-glycan bNAbs but also of a first-of-its-class N332-glycan-independent (Type-II) V3-glycan bNAb. A single immunization elicits neutralizing serum and monoclonal antibodies that are boosted and affinity matured with a heterologous immunogen. EMPEM analysis of serum antibodies, antibody cloning and cryo-EM analysis reveal that WIN332 elicits N332-glycan-independent antibodies with remarkable sequence and binding similarities with the most potent human type-I and type-II V3-glycan bNAbs. Thus, WIN332 is a promising vaccine candidate to streamline V3-glycan bNAb elicitation.

immunology↗

bioRxiv2025

in vivo Reprogramming of NG2 Glia Improves Bladder Function After Spinal Cord Injury

Neurogenic bladder is a debilitating consequence of spinal cord injury (SCI), with few treatment options that restore voluntary voiding. Here, we show that SOX2-mediated in vivo reprogramming of NG2 glia improves bladder function in a clinically relevant mouse model of contusive SCI. NG2 glia reprogramming induces adult neurogenesis, reduces glial scarring, and significantly improves urinary performance, as measured by voiding assays and conscious cystometry. Functional recovery correlates positively with neurogenesis and negatively with glial scarring. These findings demonstrate that SOX2-mediated glial reprogramming promotes autonomic repair and offers a regenerative strategy for neurogenic bladder after SCI.

neuroscience↗

bioRxiv2025

An atlas of cell type specific regulatory effects in cattle

Understanding the genetic and molecular architecture of complex traits and artificial selection is crucial for advancing sustainable precision breeding in cattle and other livestock. Yet, how genetic variation affects cellular gene expression remains elusive in cattle. Here, by integrating 8,866 bulk RNA-seq samples and 999,192 single cells of 81 cell types in 22 bovine tissues, we presented a comprehensive atlas of regulatory variants at the cell type resolution in cattle. By colocalizing with bulk-tissue expression quantitative trait loci (beQTL), we detected 57,043 novel cell-type stratified eQTL and cell-type/state interaction eQTL in 18,153 genes, which also exhibited a stronger tissue/cell-type specificity than beQTL. By examining genome-wide associations (GWAS) of 44 complex traits, these cell-resolved eQTL were colocalized with 505 (24%) additional GWAS loci compared to beQTL. Through integrating this resource with selection signatures between dairy and beef cattle, we provided tissue/cell-specific regulatory insights into cattle breeding. Overall, the current atlas of cell-type-specific regulatory variants will serve as an invaluable resource for cattle genomics and selective breeding.

genetics↗

bioRxiv2025

Unbiased recording of clonal potency reveals species-specific regulation of mammalian intestine

The mammalian intestine regenerates rapidly after damage, yet the clonal dynamics and species-specific regulation of different populations remain poorly understood. Here we used synthetic or naturally occurring DNA alterations to reconstruct clonal histories of the mouse and human intestinal epithelium at single-cell resolution. In mice, we uncovered the clonal architecture of different cell types and their roles in regeneration, supporting a hierarchical regenerative response model. We identified a rare embryonic precursor population that persisted in the adult and was crucial for regeneration after irradiation. This population was marked by Tob2, which is required for nuclear transport of Ascl2. A parallel clonal analysis of 65 human colonic biopsies revealed secretory lineage bias and an age-associated decline in clonal diversity in the distal colon. Unlike highly proliferative murine Lgr5+ stem cells, human LGR5+ cells were found largely quiescent, revealing species-specific difference in clonal potency, and suggesting a distinct regulation of intestinal stemness.

genomics↗

bioRxiv2025

Genetically Programmable Adhesive Protein Hydrogels for Sealing Perforating Corneal Trauma

The cornea, situated at the forefront of the eyeball, is often subjected to varying degrees of mechanical laceration injuries due to various traumatic incidents. Timely and precise suturing of corneal wounds to prevent the leakage of intraocular contents is a significant clinical challenge. Although some studies have attempted to use hydrogels to accurately cover corneal injuries, most of these hydrogels are only suitable for adhering to focal stromal defects that do not involve the corneal stroma. Here, a fully protein-based hydrogel, based on SpyTag-SpyCatcher chemistry, was investigated for repairing corneal perforating injury models in rats and rabbits. The hydrogel formation relies on covalent bonding between SpyTag (A) and SpyCatcher (B) under physiologically mild conditions, eliminating requirements for organic solvents, elevated temperatures, or photoactivation Notably, integration of recombinant mussel foot protein 3 (Mfp3) endowed the hydrogels with exceptional water-resistant adhesiveness, while maintaining their original mechanical properties and biocompatibility. This study demonstrates the great potential of Mfp hydrogels in the timely and precise repair of corneal perforating injuries in complex physicochemical environments. TeaserBioinspired protein hydrogel rapidly seals corneal perforations, minimizing scarring and inflammation without sutures in animal models.

bioengineering↗

bioRxiv2025

Corn rust population genomics reveals a cryptic virulent group and adaptive effectorome

Understanding the population structure of pathogens and the genetic determinants driving virulence gains is crucial for managing epidemic plant diseases. Puccinia polysora, a giga-scale fungal pathogen causing southern corn rust, has posed significant threat to global food security recently. Traditionally, P. polysora was considered clonal with minimal genetic variation. However, our population genomic and transcriptomic studies conducted in China, the emerging epicentre of the disease, have challenged this view. By adopting variant analyses appropriate to the dikaryotic nature of the pathogen, we discovered an unexpectedly clear population structure with six distinct groups. A cryptic group exhibits high virulence, facilitated by group-specific variation, and diversification of effectors. Although the Chinese population of P. polysora is predominantly asexual, internuclear exchange on some chromosomes have introduced recombination signals. The comprehensive pan-effectorome analyses revealed substantial presence/absence variation and alternative splicing events on effectors, shaping a highly adaptive effector repertoire in P. polysora. In conclusion, our findings highlight the tandem mapping on exploring clear genetic structure of dikaryotic species and reported the emergence of a virulent group and an adaptive effectorome of P. polysora. Effective containment strategies must be flexible to counter the threats posed by the unexpectedly dynamic evolution of this pathogen.

molecular biology↗

bioRxiv2025

Novel HIV-1 fusion peptide immunogens using glycan-engineered alphavirus-like particles

Immunofocusing on conserved, subdominant epitopes is critical for vaccines against highly diverse viruses such as HIV-1, influenza, and SARS-CoV-2. The eight-residue N-terminus of the HIV-1 fusion peptide (FP) is one such example of a promising yet small target. We developed new FP immunogens using three alphavirus-like particles (VLPs) and introduced additional glycans to mask shared carrier-specific epitopes. In two independent guinea pig studies, sequential immunization with heterologous carriers enhanced FP-directed antibody titers, which were further improved with glycan engineering. Separately, using diverse FP variants sharing the same N-terminal six amino acids increased neutralizing antibody titers. When combined, these two strategies led to higher FP-directed titers and, after Env trimer boosting, induced FP-directed neutralizing antibodies against multi-clade wild-type HIV-1 in nearly all animals. These findings established the importance of minimizing recurrent off-target epitopes across immunizations and support the engineered VLPs as a promising platform for peptide immunization. HighlightsO_LINovel HIV-1 fusion peptide immunogens using glycan-engineered alphavirus-like particles C_LIO_LIImproved FP-directed response by minimizing recurrent carrier-specific epitopes across immunizations C_LIO_LIImproved neutralizing response by sequential immunization with diverse FP variants C_LIO_LIFP-directed antibodies neutralizing multi-clade wildtype viruses in nearly all animals C_LI

immunology↗

bioRxiv2025

Hydrogen-Induced Calcium Influx via the TRPC4-TRPC4AP Axis

BackgroundCalcium ions (Ca{superscript 2}) serve as universal intracellular messengers regulating diverse physiological processes, while dysregulated Ca{superscript 2} homeostasis triggers cytotoxicity. Molecular hydrogen (H2) exhibits protective effects against oxidative stress-related pathologies, but its mechanism of action remains incompletely understood. Transient receptor potential canonical 4 (TRPC4) channels and their associated protein TRPC4AP are critical mediators of Ca{superscript 2} influx ( [Ca{superscript 2}]i), yet their role in H2-mediated calcium signaling is unexplored. This study investigates the molecular mechanism by which H2 modulates Ca{superscript 2} dynamics through the TRPC4-TRPC4AP axis, aiming to establish its therapeutic potential for calcium-related disorders. MethodsThe study employed heterogeneous cellular models (e.g., mesenchymal stem cells, neurons, fibroblasts) and in vivo two-photon calcium imaging in C57BL/6J mice. Techniques included CRISPR-Cas9 knockout, siRNA-mediated gene silencing, molecular docking (AlphaFold 3), and protein-protein interaction analysis. Calcium flux was quantified via fluorescence imaging, while mitochondrial integrity and cytoskeletal dynamics were assessed using JC-1 staining, ATPase activity assays, and live-cell imaging. Structural validation of TRPC4-TRPC4AP binding sites utilized mutagenesis and complementation experiments. ResultsH2 selectively enhanced extracellular Ca{superscript 2} influx via TRPC4-TRPC4AP, with no cytotoxicity or mitochondrial dysfunction observed. Key arginine residues (730Arg-731Arg) in the TRPC4 CIRB domain formed hydrogen-bond networks essential for channel activation. In vivo, H2 increased neuronal Ca{superscript 2} transient frequency and amplitude in the primary motor cortex. TRPC4AP knockout abolished H2-induced Ca{superscript 2} influx, while mutagenesis of 730Arg/731Arg disrupted channel activity. H2 also promoted cytoskeletal remodeling and cell motility, dependent on TRPC4AP-mediated Ca{superscript 2} signaling. ConclusionsThis study identifies H2 as a novel calcium agonist that activates the TRPC4-TRPC4AP axis to regulate extracellular Ca{superscript 2} influx. The 730Arg-731Arg motif in TRPC4 serves as a critical H2-sensitive site, enabling dynamic calcium homeostasis without overload. These findings provide a mechanistic basis for H2-based therapies targeting calcium dysregulation in neurodegenerative, inflammatory, and metabolic diseases, while highlighting TRPC4AP as a pivotal molecular switch for gasotransmitter signaling.

biochemistry↗