Biology subjects

Zhang, W.

Publications and source records attributed to Zhang, W..

At least 199 records · Page 11Linked to original sources

bioRxiv2025

Genome writing to dissect consequences of SVA retrotransposon disease X-Linked Dystonia Parkinsonism

Human retrotransposon insertions are often associated with diseases. In the case of the neurodegenerative X-Linked Dystonia-Parkinsonism disease, a human-specific SINE-VNTR-Alu subfamily F retrotransposon was inserted in intron 32 of the TAF1 gene. Here, we genomically rewrote a portion of the mouse Taf1 allele with the corresponding 78-kb XDP patient derived TAF1 allele. In mESCs, the presence of the intronic SVAs--rather than the hybrid gene structure--reduces hyTAF1 levels. This leads to transcriptional downregulation of genes with TATA box enriched in their promoters and triggering apoptosis. Chromatin and transcriptome profiling revealed that intronic SVAs are actively transcribed, forming barriers that likely impede transcription elongation. In mice, neuronal lineage TAF1 humanization resulted lethality of male progeny within two months. XDP male mice had severe atrophy centered on the striatum--the same affected brain region in XDP patients. Lastly, CRISPRa-mediated activation of hyTAF1 restored mESC viability, suggesting boosting TAF1 transcription as a therapeutic approach.

genetics↗

bioRxiv2025

Myelin pathology is a key feature of X-linked Dystonia Parkinsonism

X-linked Dystonia-Parkinsonism (XDP) is a progressive, adult-onset neurodegenerative movement disorder that predominantly affects males of Filipino descent1-3. The disease is caused by the insertion of a SINE-VNTR-Alu subfamily F (SVA_F) retrotransposon within an intron of the TATA-box binding protein-associated factor 1 (TAF1) gene4. A major barrier to understanding the pathophysiology of XDP has been the lack of relevant animal models. Here, we introduce a novel conditional humanized XDP mouse model harboring a hybrid mouse-human Taf1/TAF1 gene (hyTAF1) containing the pathogenic SVA_F insertion. We activated the hyTAF1 in Nestin+ neural progenitor cells and found that the resulting XDP male mice recapitulate features of the human disease including severe motor impairment, striatal atrophy, and reactive gliosis. Transcriptomic, histological, and electron microscopy analysis revealed a dramatic reduction in oligodendrocyte lineage cells and widespread myelin disruption. Consistent with these findings, postmortem brain tissue from XDP patients revealed similar myelin pathology, including near-complete loss of myelin in parts of the medial prefrontal cortex. Together, these results identify oligodendrocyte dysfunction and myelin loss as previously unrecognized contributors to XDP pathogenesis, providing new mechanistic insight into this debilitating disorder.

neuroscience↗

bioRxiv2025

High-Resolution Characterization of rAAV Genomes for Vector Quality Using Long-Read Sequencing

Recombinant adeno-associated virus (rAAV)-mediated gene therapy has been applied for human diseases. However, the rAAV capsids contain heterogeneous mixtures of full-length and truncated genomes and, depending on the manufacturing process, residual host cell and plasmid DNA. Therefore, a method is needed to characterize the encapsidated DNA of rAAV in order to support process development and batch release. The emerging long-read sequencing (LRS) has achieved AAV single-genome resolution. Here we propose a Python-based LRS profiling framework to classify and quantitate residual DNA species in rAAV products. We designed a reference that contains universal genetic components that are commonly used in rAAV production, including AmpR, KanR, Rep and Cap genes along with HPV18, Ad5 and hg38 genomes. We accessed the impurities of rAAV production from public and in-house LRS datasets. Analyzing the lambda fragments supplemented in these datasets showed that sequencing introduced size biases, which couldnt be fully corrected by regression but is improvable within library preparation. Functional potential of impurities were assessed through indicators derived from long-read alignments, which enabled us to quantitatively compare impurities between manufacturing batches. We demonstrated that LRS provides informative metrics for rAAV production and can facilitate process development to ensure therapeutic product safety and quality.

genomics↗

bioRxiv2025

Pan-cancer analysis reveals context-dependent roles of LINE-1 ORF1p in immune regulation and copy number alterations

L1 comprises 17% of the human genome, with 50-150 full-length sequences capable of retrotransposition. Although largely inactive in normal somatic tissues, tumorigenesis leads to L1 derepression and overexpression of its RNA binding chaperone protein, ORF1p. A potential cancer biomarker, ORF1p expression is a hallmark of multiple cancers and an early event in precursor lesions. Our study provides a comprehensive pan-cancer analysis of ORF1p using CPTAC proteogenomic data, revealing a dichotomous role in modulating immune responses. Integrated analyses and supervised learning models divide ORF1p-high tumors into two groups: (1) high ORF1p associates with immunosuppression, reduced interferon signaling and diminished immune cell infiltration (HNSCC and LSCC), and (2) ORF1p-high tumors associate with immune activation (UCEC). Linear regression models reveal that cancer-specific aneuploidies may underlie this immune dichotomy, highlighting the prognostic significance of ORF1p and informing new strategies to leverage detection of plasma-circulating ORF1p to enhance immunotherapeutic efficacy in different tumor contexts.

genomics↗

bioRxiv2025

De Novo Design of Anti-Aging Peptides

Aging, a universal biological process in complex organisms, is increasingly recognized to be driven by progressive loss of epigenetic information, as proposed in the Information Theory of Aging (ITOA). However, research on anti-aging peptides remains scarce, with most existing efforts confined to derivatives of natural proteins, while systematic design attempts are virtually absent. This limitation not only restricts discovery within the evolutionary sequence space but also hampers the identification of candidates with novel mechanisms and improved efficacy. Here, we present ElixirSeeker2, the first computational framework for de novo design of anti-aging peptides. By integrating modeling of known anti-aging peptides, activity scoring from the IC50 database, and penalty constraints from toxic peptides, ElixirSeeker2 enables large-scale virtual screening and identification of novel peptide candidates. Several lead peptides demonstrated significant effects in delaying cellular senescence, restoring cellular functions in vitro and in enhancing locomotor activity of aged Caenorhabditis elegans. This study not only validates the feasibility of de novo design in anti-aging interventions but also establishes a strategy for the development of next-generation biologics.

bioinformatics↗

bioRxiv2025

Integrative multi-modal analysis reveals the contribution of noncoding RNAs to post-treatment progression of IDH-mutant astrocytomas

IDH-mutant (IDHmut) astrocytomas typically arise as grade 2-3 tumors, but a subset of them progress to grade 4 after treatment, significantly worsening the prognosis. It is unresolved how noncoding RNAs (ncRNAs) contribute to this tumor progression. To characterize ncRNAs regulatory roles, we profiled and analyzed the coding and noncoding transcriptomes of matched tumor samples before and after progression to grade 4 in IDHmut astrocytoma patients. By integrating our data with public primary and matched tumor cohorts, we found that upregulated protein-coding genes in progressed tumors overlapped with those in primary grade 4 tumors and were linked to cell proliferation. In contrast, downregulated genes differed between primary and post-treatment grade 4 tumors. A large fraction of genes that were downregulated only in the post-treatment setting were associated with decreased cell differentiation. We identified 53 progression-related ncRNAs predicted to regulate 125 differentially expressed genes. Gene regulatory network analysis revealed their involvement in cell cycle control, extracellular matrix (ECM) organization, and neural differentiation. Notably, hsa-let-7b-3p, a tumor suppressor microRNA, showed recurrent hemizygous deletions and downregulation after post-therapy progression. The long noncoding RNA (lncRNA) PVT1 was recurrently gained and upregulated in grade 4 tumors. The lncRNA NEAT1, previously linked to treatment resistance, was especially upregulated post-treatment and had the highest number of predicted targets (n=38), many related to ECM organization. Overall, our findings highlight the role of ncRNAs in the post-treatment progression of IDHmut astrocytomas, offering new insights into mechanisms of their malignancy.

cancer biology↗

bioRxiv2025

A Pangenomic Method for Establishing a Somatic Variant Detection Resource in HapMap Mixtures

Somatic mosaicism is essential in human biology and disease, yet robust benchmarks are scarce. The SMaHT Consortium mixed six HapMap cell lines to create artificial somatic variants spanning 0.25% to 16.5% variant allele fractions. We developed a technology-agnostic method that builds pangenome graphs from individual assemblies to create unified benchmarking sets: > 6M single-nucleotide variants, 1.8M small insertions/deletions, 49K structural variations, and 10K mobile element insertions across autosomes, X, and mitochondrial chromosomes. We validated the variants using ultra-deep simulated reads and developed a binomial-based model to estimate coverage requirements for variant detection. Evaluating multiple callers showed CHM13 alignment improves structural variant detection and offers advantages in difficult-to-map regions compared to GRCh38. Systematic characterization showed regions with low detection rate are enriched in centromeres, satellite sequences, tandem repeats, and falsely duplicated genes. This accurate, versatile resource enables systematic evaluation of somatic variant detection technologies.

genomics↗

bioRxiv2025

NQO1 phase condensation promotes stress granule assembly to facilitate pancreatic carcinogenesis

G3BP1 promotes pancreatic ductal adenocarcinoma (PDAC) tumorigenesis driven by oncogenic KRAS mutations through liquid-liquid phase separation (LLPS)-mediated assembly of stress granules (SGs). However, the regulatory mechanisms remain elusive. We identify the antioxidant enzyme NAD(P)H quinone dehydrogenase 1 (NQO1) as a novel SG regulator that enhances SG assembly in pancreatic cancer cells independently of reactive oxygen species (ROS). Mechanistic studies reveal that NQO1 does not regulate the expression of G3BP1 or other SG-associated genes. Instead, NQO1 undergoes LLPS dependent on its RNA-binding K homology (KH) like domain. Further analysis demonstrates that residues 121-131 of NQO1 directly interact with G3BP1s RNA-binding domain (RBD), enhancing the multivalency of G3BP1 complexes to potentiate LLPS-driven SG assembly. This interaction accelerates cell proliferation, KRAS mutation-induced acinar-to-ductal metaplasia (ADM), and pancreatic carcinogenesis. Notably, the interaction between NQO1 residues 121-131 and G3BP1s RBD is essential for NQO1 phase condensation under stress condition. Integrative analysis of human PDAC transcriptomic datasets reveals a weak association between NQO1 and G3BP1 levels. Importantly, both NQO1 and G3BP1 formed biological condensates and co-localized in the lesions of human PDAC tissue sections. Our study uncovers a novel KRAS mutation-driven mechanism of pancreatic carcinogenesis through the lens of phase separation, transcending conventional gene expression regulation and offering new insights into non-canonical KRAS-NQO1-G3BP1-SG regulatory networks in PDAC initiation.

cancer biology↗

bioRxiv2025

Phosphoantigen-Driven Dissociation of Butyrophilin Oligomers Activates γδ T Cells

{gamma}{delta} T cells represent a promising avenue for cancer immunotherapy. The V{gamma}9V{delta}2 T cell receptor (TCR), expressed by the predominant subset of {gamma}{delta} T cells, responds to phosphoantigen (pAg)-engaged butyrophilins (BTNs) on various cancer cells. However, the molecular mechanism underlying pAg-mediated activation of V{gamma}9V{delta}2 TCRs remains a subject of debate. Here, we employed an integrative approach to elucidate the mechanism of pAg reactivity in V{gamma}9V{delta}2 T cells. Our results demonstrate that BTNs form higher-order oligomers in the absence of pAg. Upon pAg binding, these oligomers dissociate into tetramers, enabling V{gamma}9V{delta}2 TCR engagement. This pAg-induced dissociation of higher-order BTN complexes is critical for pAg-mediated activation of {gamma}{delta} T cells. Our findings reveal a mechanism of BTN dissociation-driven pAg sensing, providing valuable insight for future immunotherapeutic strategies.

immunology↗

bioRxiv2025

Dual Targeting of IKKβ and NR4A1 for AML Therapy

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor clinical outcomes and limited therapeutic options. Aberrant activation of the IKK{beta}-NF-{kappa}B pathway occurs in approximately 40% of AML cases and contributes to leukemogenesis. However, pharmacological inhibition of IKK{beta} has been limited by serious toxicities, including neutrophilia. Here we identify IKK{beta} and NR4A1 as critical drivers of AML progression in certain models and develop a proteolysis-targeting chimera (PROTAC) capable of degrading the proteins. Although NR4A1 has previously been described as a tumor suppressor in AML, our findings demonstrate that NR4A1 exhibits oncogenic functions in some AMLs of the (pro)monocytic lineage. Notably, elevated expression of IKK{beta} and NR4A1 in AML is associated with poor clinical outcomes, playing non-redundant oncogenic roles in AML. To therapeutically target IKK{beta} and NR4A1, we designed and synthesized a series of celastrol-based PROTACs that exploit celastrols ability to bind both IKK{beta} and NR4A1. Among these compounds, the lead A9 induces potent cytotoxicity in multiple AML cell lines and primary AML samples through cereblon E3 ligase-dependent degradation of IKK{beta} and/or NR4A1. In vivo, A9 suppresses leukemia progression in a KMT2A::MLLT3 AML mouse model without inducing neutrophilia, supporting PROTAC-mediated degradation of IKK{beta} and NR4A1 as a promising therapeutic strategy. Plain language summaryAcute myeloid leukemia (AML) is a predominant form of blood cancer with devastating consequences in both young and adult populations. Despite some advances in AML treatment over the last decade, there is still an unmet medical need to develop new drugs for difficult-to- treat AMLs. We discover that two proteins, namely IKK{beta} and NR4A1, play important roles in promoting the AML disease and could be associated with more severe AML subtypes. To target and destroy those proteins within AML cells, we employ a novel targeted protein degradation approach, which involved design, synthesis, and screening of PROTAC drugs, to discover a drug possessing pronounced AML cell killing activity by virtue of IKK{beta} and NR4A1 degradations. The drug also significantly reduces AML progression in mice without any noticeable adverse effects. Our current efforts involve more comprehensively testing the benefit of the drug (and its analogs) in a wide range of clinically relevant AML models. Key PointsO_LIIKK{beta} and NR4A1 are clinically relevant drivers of AML pathogenesis. C_LIO_LIA novel celastrol-based PROTAC can effectively degrade IKK{beta} and/or NR4A1 to potentially treat AML. C_LI

cancer biology↗

bioRxiv2025

Discovery of circulating cell-free DNA 5hmC biomarkers for peritoneal metastasis in colorectal and appendiceal cancer

IntroductionPeritoneal metastases (PM) are associated with poor prognosis in patients with colorectal cancer (CRC) or appendiceal adenocarcinoma (AA), yet detection of PM is unreliable using current circulating DNA technology. Leveraging novel 5hmC-seal technology to detect ultra-low amounts of DNA in plasma, we demonstrate the feasibility of 5-hydroxymethylcytosine (5hmC) signatures derived from circulating cell-free DNA (cfDNA) as biomarkers for PM. MethodsUsing a highly sensitive and robust 5hmC sequencing approach on genomic DNA isolated from peripheral blood samples, we developed predictive models to identify biomarkers for peritoneal metastases. ResultsWe obtained genome-wide 5hmC profiles from 71 CRC/AA patients with PM, 41 without PM, and 73 non-cancer controls. Predictive models trained on genomic region 5hmC levels in patients with cancer could distinguish PM status with high sensitivity and moderate specificity (AUC 0.827, sensitivity 92.4%, specificity 46.1%). Pathway enrichment analysis identified epigenetically dysregulated cancer, cell migration, adhesion, and immune-related pathways in PM. ConclusionNovel 5hmC-Seal technology based 5hmC signatures can detect patients with peritoneal metastases from CRC and AA, albeit with reduced specificity. This study lays a foundation for future clinical assay development for PM. Statement of significanceWe demonstrate high-sensitivity detection of peritoneal metastasis in colorectal and appendiceal adenocarcinomas using 5hmC-Seal of plasma cfDNA. Earlier detection of this condition could expand curative treatments in [~]20,000 affected U.S. patients.

cancer biology↗

bioRxiv2025

X-intNMF: A Cross- and Intra-Omics Regularized NMF Framework for Multi-Omics Integration

MotivationThe rapid accumulation of multi-omics data presents a valuable opportunity to advance our understanding of complex diseases and biological systems, driving the development of integrative computational methods. However, the complexity of biological processes--spanning multiple molecular layers and involving intricate regulatory interactions--requires models that can capture both intra- and cross-omics relationships. Most existing integration methods primarily focus on sample-level similarities or intra-omics feature interactions, often neglecting the interactions across different omics layers. This limitation can result in the loss of critical biological information and suboptimal performance. To address this gap, we propose X-intNMF, a network-regularized non-negative matrix factorization (NMF) model that explicitly incorporates both cross-omics and intra-omics feature interaction networks during multi-omics integration. By modeling these multi-layered relationships, X-intNMF enhances the representation of biological interactions and improves integration quality and prediction accuracy. ResultsFor evaluation, we applied X-intNMF to predict breast cancer phenotypes and classify clinical outcomes in lung and ovarian cancers using mRNA expression, microRNA expression, and DNA methylation data from TCGA. The results show that X-intNMF consistently outperforms state-of-the-art methods. Ablation studies confirm that incorporating both cross-omics and intra-omics interactions contributes significantly to the models improved performance. Additionally, survival analysis demonstrates that the integrated multi-omics representation offers strong prognostic value for both overall survival and disease-free status. These findings highlight X-intNMFs ability to effectively model multi-layered molecular interactions while maintaining interpretability, robustness, and scalability within the NMF framework. Availability and implementationSource code is available at: https://github.com/compbiolabucf/X-intNMF

bioinformatics↗

bioRxiv2025

SynOmics: Integrating Multi-omics Data Through Feature Interaction Networks

The integration of multi-omics data is essential for achieving a comprehensive understanding of molecular systems and enhancing the performance of predictive models in biomedical research. However, many existing models have limited capacity to capture cross-omics feature interactions, which hinders the depth of integration. In this study, we introduce SynOmics, a graph convolutional network framework designed to improve multi-omics integration by constructing omics networks in the feature space and modeling both within- and cross-omics dependencies. By incorporating both omics-specific networks and cross-omics bipartite networks, SynOmics enables simultaneous learning of intra-omics and interomics relationships. Unlike traditional approaches that rely on early or late integration strategies, SynOmics adopts a parallel learning strategy to process feature-level interactions at each layer of the model. Experimental results demonstrate that SynOmics consistently outperforms state-of-the-art multi-omics integration methods across a range of biomedical classification tasks, highlighting its potential for biomarker discovery and clinical applications. AvailabilitySource code is available at https://github.com/compbiolabucf/SynOmics. Supplementary informationSupplementary data are available at Journal Name online.

bioinformatics↗

bioRxiv2025

Bodily Self in Macaque Monkeys and Human Infants

Whether monkeys possess the concept of bodily self remains controversial. We found that macaque monkeys trained for mirror self-recognition (MSR) could spontaneously recognize themselves when viewing video images of their back from a third-person perspective (3PP), but this generalization required a few minutes of "exploration". In contrast, through visual-tactile synchronization training similar to that used in human out-of-body studies, naive monkeys could recognize themselves from 3PP back images and demonstrated MSR within seconds. Interestingly, in human infants, we found that 3PP back self-recognition developed spontaneously several months after MSR. These results demonstrate the existence of hierarchical bodily self in macaques and similar stepwise development of bodily self in human infants, offering insights into the emergence and manifestation of bodily self in natural and artificial intelligence.

neuroscience↗

bioRxiv2025

FoxP3 forms a head-to-head dimer in vivo and stabilizes its multimerization on adjacent microsatellites

FoxP3, the master regulator of Tregs, employs two DNA-binding modes to recognize diverse DNA sequences. It multimerizes on long TnG repeats (n = 2-5) to bridge DNA segments and stabilize chromatin loops, and it forms head-to-head (H-H) dimers on inverted repeat forkhead motifs (IR-FKHM) without bridging DNA. Although genomic data confirm its multimeric role, in vivo evidence for H-H dimerization has been elusive. Here, unbiased pull-down sequencing uncovers a range of relaxed motifs that drive H-H dimerization, enabling systematic genome- wide analysis. We demonstrate that FoxP3 binds genomic DNA as both H-H dimers and multimers in Tregs, with H-H binding often seeding and stabilizing multimerization on adjacent TnG repeats--especially on shorter, suboptimal repeats. While multimerization is conserved across FoxP family members, H-H dimerization is unique to FoxP3 orthologs, conferred by its divergent accessory loop. This dual-mode strategy broadens FoxP3s sequence repertoire and enhances its architectural function in chromatin looping.

bioinformatics↗

bioRxiv2025

Challenges to case-only analysis for gene-environment interaction detection using polygenic risk scores: model assumptions and biases in large biobanks

Gene-environment interaction is important for studying complex diseases. Case-only analysis has been proposed to improve power for GxE detection. However, case-only analysis relies on key assumptions, including correct specification of the disease risk model and marginal independence between genetic and environmental variables. In this study, we systematically investigate the challenges of case-only analysis using polygenic risk scores (PRS) as genetic variables in large biobanks. Through simulations, we demonstrate that the false positive control of PRS-based case-only analysis depends on the log-linear disease risk model and weak main effects, and that it is prone to false positives under other commonly used disease risk models. We then conduct case-only analyses for breast cancer, prostate cancer, class 3 obesity, and short stature in the UK Biobank, using PRS derived from non-overlapping chromosome sets (e.g., even-numbered and odd-numbered chromosomes) that are unlikely to interact with each other. The resulting case-only regression estimates consistently show negative shifts compared to population-based estimates, suggesting false positives driven by collider bias due to model misspecification. Furthermore, correlations between chromosome set-specific PRS, likely driven by assortative mating or population stratification, suggest additional sources of confounding. Our results underscore the challenges of applying PRS-based case-only analysis in large biobank settings and highlight the need for caution when interpreting case-only results.

genetics↗

bioRxiv2025

The two-component nuclease-active KELShedu system confers broad antiphage activity via abortive infection

Bacteriophages and bacteria engage in a continuous evolutionary arms race, driving the development of intricate bacterial defense systems such as CRISPR-Cas, BREX, Gabija, and Shedu. Here, we characterize a two-component KELShedu system in Escherichia coli that confers resistance to phages via abortive infection. The KELShedu system comprises KELA, a dsDNA-binding protein, and KELB, a metal ion-dependent nuclease harboring the DUF4263 domain. In addition, we find that physiological levels of NTP inhibit the DNA cleavage activity of the KELShedu system, suggesting that KELShedus activation depends on reduced intracellular NTP levels during phage invasion. Our research demonstrates that the KELShedu system responds to nucleotide depletion triggered by phage replication, leading to non-specific degradation of cellular DNA and ultimately inducing abortive infection. These insights into the KELShedu system expand the repertoire of bacterial anti-phage mechanisms and lay the groundwork for novel applications in microbial engineering and therapeutic development. TeaserThe KELShedu system exerts anti-phage function by aborting infection in response to physiological changes following phage infection

microbiology↗

bioRxiv2025

Resolving the estrogen paradox in hereditary retinal degeneration: Esr1 activation suppresses Tnf-α signaling as a photoreceptor self-protection mechanism

Retinitis pigmentosa (RP) is an inherited retinal degenerative disorder characterized by progressive photoreceptor loss and irreversible blindness. Increasing evidence implicates neuroinflammation as a contributor to photoreceptor degeneration extending beyond the initial genetic insult. Although estrogen has been reported to exert anti-inflammatory effects in the central nervous system, its role in RP remains controversial, with some studies suggesting a paradoxical exacerbation of retinal pathology. To address this discrepancy, we identify estrogen receptor alpha (Esr1) as a central immunoregulatory hub in RP. Transcriptomic analyses of rd1 and rd10 revealed upregulation of estrogen-responsive and inflammatory pathways, with Esr1 expression markedly elevated during degeneration. TUNEL assays demonstrated that systemic estradiol (E2) exerted divergent effects, protective in rd1 yet deleterious in rd10, whereas selective pharmacological activation of Esr1 with propyl pyrazole triol (PPT) consistently reduced photoreceptor death, preserved dark-adapted ERG responses, and downregulated inflammatory mediators including Tnf-, Cx3cl1/Cx3cr1, Cd68, and Iba1. Mechanistically, Esr1 activation repressed microglial Tnf transcription and disrupted a self-sustaining Cx3cl1/Cx3cr1-Tnf- signaling loop driving microglial recruitment, activation and neurotoxicity in the outer nuclear layer (ONL). Targeted interventions confirmed tumor necrosis factor receptor 1 (Tnfr1) as the principal mediator of Tnf-induced photoreceptor death: selective inhibition with R7050 conferred superior protection compared with broad-spectrum Tnf- inhibitors (etanercept, infliximab). Cx3cr1 blockade likewise suppressed microglial activation and improved visual outcomes. Collectively, our findings establish Esr1 activation as not merely an external intervention but the amplification of an intrinsic self-protective program, positioning Esr1, Tnfr1, and Cx3cr1 as actionable therapeutic targets to suppress neuroinflammation and preserve vision in RP and related retinal disorders.

neuroscience↗