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{"title":"Proteomic Insights Into the Therapeutic Effects of the Camel Milk-Derived Peptide on Insulin Resistance: Modulation of Metabolic, Oxidative, and Signaling Pathways","authors":"Issoufou Katambe Mohamed, Yufei Hua, Xiangzhen Kong, Xingfei Li, Yeming Chen, Caimeng Zhang, Mouhamed Fall, Abuubakar Hassan Ramadhan","doi":"10.20944/preprints202512.1664.v1","DOIUrl":"https://doi.org/10.20944/preprints202512.1664.v1","url":null,"abstract":"Insulin resistance (IR) is a hallmark of type 2 diabetes, characterized by disrupted metabolic regulation, oxidative stress, and altered cell signaling. This study employed Data-Independent Acquisition (DIA) quantitative proteomics to profile the proteomic landscape in a cellular model of insulin resistance (MOD) and to evaluate the therapeutic effects of camel milk derived peptide TYYPPQ. Principal Component Analysis (PCA) confirmed distinct proteomic profiles between healthy control (C), MOD, and P2-treated cells, indicating that TYYPPQ induced a partial but significant reprogramming of the insulin-resistant proteome. Enrichment analyses (GO and KEGG) revealed that insulin resistance was characterized by widespread dysregulation, including increased endoplasmic reticulum (ER) stress, oxidative stress, inflammatory pathways, and disruptions in sphingolipid and fructose metabolism. In contrast, TYYPPQ treatment promoted a recovery signature, significantly enriching pathways related to improved insulin signaling (PI3K-Akt, AMPK), regulation of lipolysis, amino acid metabolism, actin cytoskeleton organization, and a marked reduction in ER stress markers. Crucially, these pathway predictions were validated at the molecular level, as qPCR and Western blot analysis confirmed that TYYPPQ effectively restored the expression and phosphorylation of AMPK. Further domain and subcellular localization analyses indicated that insulin resistance disrupted mitochondrial, redox, and protein homeostasis, while P2 treatment counteracted these effects by modulating domains related to mitochondrial function (proline dehydrogenase, cytochrome c oxidase) and restoring protein distribution, notably reducing ER-localized proteins. Collectively, these multi-faceted proteomic findings demonstrate that the peptide TYYPPQ mitigates insulin resistance by coordinately restoring key metabolic and signaling pathways, reducing cellular stress, and improving mitochondrial and cytoskeletal function, highlighting its potential as a therapeutic agent.","PeriodicalId":521283,"journal":{"name":"Preprints.org","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.preprints.org/frontend/manuscript/9f0d53a1f119876bcaacb81044e1907d/download_pub","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147907123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Synergistic Stabilization Strategy for Room-Temperature Internal Gelation Process: From Zirconia Surrogates to Uranium Fuel Microspheres","authors":"Rui Xu, Xiao Yuan, Jianjun Li, Changsheng Deng, Z. Li, Xingyu Zhao, Shaochang Hao, Bing Liu, Yaping Tang, Jingtao Ma","doi":"10.20944/preprints202512.1488.v1","DOIUrl":"https://doi.org/10.20944/preprints202512.1488.v1","url":null,"abstract":"The internal gelation process is essential for producing spherical nuclear fuel micro-spheres. However, its application is constrained by the poor room-temperature stability of conventional broths and by the inherent trade-off between stability and strength. A novel five-component broth system (ZrO(NO₃)₂-HMTA-urea-acetylacetone (ACAC)-glucose) was developed. The synergistic effects of ACAC and glucose on sol stability and gelation ki-netics were systematically investigated. An optimal ACAC/glucose molar ratio of 1:1 and an ACAC/ZrO2+ ratio of 1.5 were identified, yielding a broth stable for over 5 h at 25°C. The resulting yttrium stabilized zirconia (YSZ) microspheres exhibited excellent sphericity (1.04±0.01), density (5.84 g/cm³), and crushing strength (8.0 kg/sphere). This stabilization strategy was successfully extended to a uranium system, enhancing its room-temperature stability from minutes to 6 h. The work demonstrates that the synergistic ACAC-glucose system effectively decouples the stability-strength dilemma. Its successful application to a uranium broth confirms the broader utility of the dicarbonyl complexation strategy, providing an energy-efficient route for producing high-quality nuclear fuel microspheres.","PeriodicalId":521283,"journal":{"name":"Preprints.org","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.preprints.org/frontend/manuscript/a135c00a0aa43ca30fa01fb94b9e5471/download_pub","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147893878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-Trait Genetic Association Reveal a Central Mechanism in the Comorbidity of Hyperuricemia and Hyperlipidemia","authors":"Shujia Liu, Xinyu Feng, X H Liu, Yan Lin, Bing Zhang, Yu Wang, Zhijian Lin, Xiaomeng Zhang","doi":"10.20944/preprints202512.0761.v1","DOIUrl":"https://doi.org/10.20944/preprints202512.0761.v1","url":null,"abstract":"Background: Hyperuricemia and hyperlipidemia frequently coexist in metabolic syndrome, yet their shared pathogenic mechanisms remain insufficiently elucidated. Identifying convergent molecular pathways may provide novel therapeutic targets for metabolic comorbidity. Methods: A multi-omics strategy integrating multi-trait genome-wide association analysis (MTAG), weighted gene co-expression network analysis (WGCNA), protein–protein interaction (PPI) network construction, and functional enrichment analysis was employed to identify common genetic drivers of hyperuricemia and hyperlipidemia. To validate the bioinformatic findings, a high-purine and high-fat diet-induced quail model of combined hyperuricemia and hyperlipidemia was established, and the expression levels of NAMPT and SIRT1 were assessed in serum and metabolic tissues. Results: Multi-trait genetic association analysis revealed that the NAMPT–SIRT1 signaling pathway demonstrated a 66.7% genetic overlap and a 100% target gene detection rate, accompanied by significant enrichment in the nicotinamide metabolic pathway (P=2.1×10-12). In vivo validation showed markedly decreased expression of NAMPT and SIRT1 in both serum and liver tissues of comorbid model animals, aligning with the predicted molecular dysregulation pattern. Conclusion: By integrating multi-omics screening with experimental validation in an avian model, this study highlights the NAMPT–SIRT1 axis as a core molecular hub linking hyperuricemia and hyperlipidemia. These findings provide mechanistic insight into metabolic comorbidity and suggest NAMPT–SIRT1 signaling as a promising target for therapeutic intervention and drug development.","PeriodicalId":521283,"journal":{"name":"Preprints.org","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.preprints.org/frontend/manuscript/7979fe84b33dfd0f9f047d350bcaa998/download_pub","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147382102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein Aggregation and Proteostasis Failure in Neurodegenerative Diseases: Mechanisms, Structural Insights, and Therapeutic Strategies","authors":"Jamir Pitton Rissardo, Ana Letícia Fornari Caprara","doi":"10.20944/preprints202512.0638.v1","DOIUrl":"https://doi.org/10.20944/preprints202512.0638.v1","url":null,"abstract":"Protein aggregation is a defining pathological hallmark of major neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and tauopathies. These disorders share a convergent failure of proteostasis—the integrated network that regulates protein synthesis, folding, trafficking, and clearance—rather than isolated, disease-specific anomalies. Neurons, as long-lived post-mitotic cells, are particularly vulnerable to proteostasis collapse, which promotes accumulation of misfolded proteins such as amyloid-β, α-synuclein, tau, and TDP-43. Aggregates exhibit structural polymorphism, prion-like propagation, and strain-specific conformations that dictate regional vulnerability and clinical heterogeneity. Mechanistically, clearance pathways—including the ubiquitin–proteasome system, autophagy–lysosomal axis, endosomal–lysosomal trafficking, and molecular chaperones—operate in a highly coordinated manner; their dysfunction accelerates aggregation and neurotoxicity. Emerging evidence implicates liquid-liquid phase separation as a precursor to amyloid formation, while post-translational modifications such as phosphorylation, ubiquitination, and truncation modulate aggregation kinetics and pathogenicity. Aging further exacerbates proteostasis failure through impaired autophagic flux, lysosomal dysfunction, and glymphatic clearance decline, amplifying aggregate burden and prion-like dissemination. Despite extensive development of aggregation inhibitors, immunotherapies, and proteostasis enhancers, clinical translation remains limited due to poor blood–brain barrier penetration, off-target effects, and incomplete understanding of intermediate toxic species. Future strategies should integrate structural biology, seed amplification assays, and systems-level approaches to target early aggregation events, reinforce clearance pathways, and modulate neuroinflammation. This review synthesizes mechanistic insights, structural data, and therapeutic advances, emphasizing the complexity of protein aggregation as a dynamic, multifactorial process in neurodegeneration.","PeriodicalId":521283,"journal":{"name":"Preprints.org","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.preprints.org/frontend/manuscript/46e76701e11be03ff59355c99adf9b88/download_pub","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147895659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reaction–Diffusion Model of CAR-T Cell Therapy in Solid Tumours with Antigen Escape","authors":"Maxim Polyakov, Elena Ivanovna Tuchina","doi":"10.20944/preprints202512.0136.v1","DOIUrl":"https://doi.org/10.20944/preprints202512.0136.v1","url":null,"abstract":"Developing effective CAR-T cell therapy for solid tumours remains challenging because of biological barriers such as antigen escape and an immunosuppressive microenvironment. The aim of this study is to develop a mathematical model of the spatio-temporal dynamics of tumour processes in order to assess key factors that limit treatment efficacy. We propose a reaction–diffusion model described by a system of partial differential equations for the densities of tumour cells and CAR-T cells, the concentration of immune inhibitors, and the degree of antigen escape. The methods of investigation include stability analysis and numerical solution of the model using a finite-difference scheme. The simulation results show that antigen escape leads to the formation of a persistent core within the tumour and subsequent relapse after an initial regression. We find that the efficacy of therapy critically depends on the balance between the rate of tumour-cell killing and the rate of resistance development, and that repeated administration of CAR-T cells provides deeper and more durable suppression of tumour growth compared with a single infusion. We conclude that the proposed model is a valuable tool for analysing and optimising CAR-T therapy protocols, and that our results highlight the need for combined strategies aimed at overcoming antigen escape.","PeriodicalId":521283,"journal":{"name":"Preprints.org","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.preprints.org/frontend/manuscript/65575bd211c3c4727956734bf3d95df3/download_pub","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147902136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subinhibitory Metronidazole Enhances Production, Virulence Factor Loading, and Endothelial Cytotoxicity of <em>Porphyromonas gingivalis</em> Extracellular Vesicles","authors":"Zixiang Wu, Xia Li, Ge Song","doi":"10.20944/preprints202512.0030.v1","DOIUrl":"https://doi.org/10.20944/preprints202512.0030.v1","url":null,"abstract":"Objectives: Porphyromonas gingivalis (P. gingivalis), a key periodontal pathogen, has been linked to atherosclerosis development. The clinical failure of antibiotics to improve cardiovascular outcomes necessitates alternative explanations. This study examines how sub-minimal inhibitory concentrations (sub-MIC) of metronidazole affect the biogenesis and pathogenic potential of P. gingivalis extracellular vesicles (EVs) on human umbilical vein endothelial cells (HUVECs). Design: EVs were isolated from untreated (N-EVs) and sub-MIC metronidazole-treated (M-EVs) bacteria through ultracentrifugation. Characterization included TEM, nanoparticle tracking analysis, and Western blotting for virulence factors. HUVECs were evaluated using viability, migration, cell death assays, ROS detection, NF-κB activation imaging, and cytokine measurement. Results: Sub-MIC metronidazole increased EVs production by 2.3-fold and enriched M-EVs with virulence factors (lipid A LPS, Kgp, RgpA). M-EVs demonstrated significantly stronger cytotoxicity, causing greater impairment of HUVEC viability and migration, alongside increased cell death. Mechanistically, M-EVs induced elevated mitochondrial and cellular ROS, promoting NF-κB activation and enhancing secretion of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Conclusion: Sub-MIC metronidazole exacerbates endothelial injury by amplifying EV production and virulence factor loading in P. gingivalis, offering a mechanistic explanation for the limited cardiovascular benefits of antibiotic therapy in periodontitis patients.","PeriodicalId":521283,"journal":{"name":"Preprints.org","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.preprints.org/frontend/manuscript/cad43093709ef3e0a7e302f9126962dd/download_pub","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147905068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<em>Bacillus marisflavi</em> XJ-04 Prevention of Watermelon Sclerotiniose and the Study of Biocontrol Effect","authors":"Lingyue Zhu, Xiaomei Wang","doi":"10.20944/preprints202511.2310.v1","DOIUrl":"https://doi.org/10.20944/preprints202511.2310.v1","url":null,"abstract":"With the increase of watermelon cultivation area and continuous cropping, the harm of watermelon sclerotiniosis is becoming more and more serious. It has now risen to an important disease in watermelon production, which seriously affects the quality and yield of watermelon. The pathogen of watermelon Sclerotinia sclerotiorum is [Sclerotinia sclerotiorum(Lib.) De Bary], which is widely distributed in the world, causes plant sclerotia worldwide. The host range of Sclerotinia sclerotiorum is very wide, which not only harms watermelon, but also infects 75 families, 278 genera and 450 species of Cucurbitaceae, Leguminosae, Solanaceae and Cruciferae. To provide a new control method for the biological control of sclerotinia sclerotiorum in watermelon, the biocontrol bacteria in soil were isolated, screened and identified, and the bacteriostasis was studied. (1) The isolation, identification and biological characteristics of the pathogenic bacteria were determined. The fungus strain LY 24 was obtained from watermelon stem and vine infected with Sclerotinia sclerotiorum. The fungus strain LY 24 had good pathogenicity to watermelon plants by pathogenicity. The strain LY 24 was identified by morphology and molecular biology. The results showed that the best carbon source of strain LY 24 was mannitol, the best nitrogen source was tryptone, the best inorganic salt was NaCl, the best pH value was 9.The best growth temperature was 25℃, and the best light condition was whole darkness. (2) The isolation and identification of biocontrol bacteria in soil were carried out in the watermelon planting base around Changchun, such as the watermelon planting base in Jiutai District. Forty soil samples around the rhizosphere of watermelon plants were collected, and 300 strains of bacteria were isolated from the samples. The bacterial strains with significant antagonistic effect were obtained by plate confrontation method, and the strain XJ-04 with good antibacterial effect was selected as the research object. The inhibitory band width of strain XJ-04 was about 5.21 mm. The inhibitory rate of strain XJ-04 against Sclerotinia sclerotiorum was 70.12%. After morphological and molecular biological identification, strain XJ-04 was identified as Bacillus marisflavi. The physiological and biochemical characteristics of biocontrol strain XJ-04 were analyzed by detecting Gram reaction, contact enzyme reaction, methyl red reaction, V-P reaction and hydrogen sulfide reaction. (3) Studies on fermentation optimization of strain and fermentation broth stability. The optimum composition of culture medium was determined by orthogonal test, which was No.8 culture medium (sucrose, fine bran, K2HPO4·3H2O, pH 9). The inhibition rate was about 71.75%. The optimum addition amount of the above three components was determined by response surface methodology. When the addition amounts of sucrose, fine bran and K2HPO4·3H2O were about 21.08 g/L, 9.17 g/L and 9.77 g/L respectively, the highest inhibit","PeriodicalId":521283,"journal":{"name":"Preprints.org","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.preprints.org/frontend/manuscript/9d19ba7fcd3bfeaf701590a7975e0467/download_pub","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147879154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"More Studies of the Deranged Myelinotrophic Factors in Multiple Sclerosis Central Nervous System Are Needed to Clarify Their Pathogenic Meaning","authors":"Giuseppe Scalabrino","doi":"10.20944/preprints202511.2114.v1","DOIUrl":"https://doi.org/10.20944/preprints202511.2114.v1","url":null,"abstract":"Many molecules (mainly growth factors and/or cytokines) are produced by human central nervous system (CNS) cells and may positively or negatively influence oligodendrogenesis, proliferation, and the migration of oligodendrocyte precursor cells (OPCs). Multiple sclerosis (MS) leads to the destruction of CNS myelin sheaths and myelin-producing oligodendrocytes (ODCs). This review considers the few published studies of platelet-derived growth factor (PDGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and ciliary-neurotrophic factor (CNTF) in cerebrospinal fluid and/or post-mortem CNS samples which, like previously reviewed studies of epidermal growth factor (EGF), have shown deranged levels in MS, and also considers the abnormal levels of Nuclear Factor kappa-light-chain-enhancer of activated B cells and some microRNAs in MS CNS. The derangements of all of these molecules in MS CNS surely hinder ODC differentiation, proliferation, and migration, and ultimately they contribute to remyelination failure. Despite the differences between MS and experimental autoimmune encephalomyelitis (EAE), it is also worth noting that the individual administration of PDGF, BDNF, CTNF, and EGF prevents the onset and/or “cures” EAE in mice, and so, together with findings concerning other aspects of MS, the results of the reviewed studies seem to support the idea that MS demyelination is a consequence of oligodendrocytopathy followed by an autoimmunity reaction.","PeriodicalId":521283,"journal":{"name":"Preprints.org","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.preprints.org/frontend/manuscript/97a7f6196848a2fbf84ebfe378b717b7/download_pub","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147917843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AraR Transcription Factor: The Mastermind behind Sugar Metabolism and Acid Tolerance","authors":"Lili Zhao, Mengrong Chen, Changzhen Fu, Tao Pan, Qiling Chen","doi":"10.20944/preprints202511.2051.v1","DOIUrl":"https://doi.org/10.20944/preprints202511.2051.v1","url":null,"abstract":"Microorganism employs sophisticated strategies to adapt to acidic environments, with transcription factors occupying pivotal nodes within their hierarchical regulatory networks. In this study, we performed functional characterization of the AraR transcription factor LP_RS14895 via integrated multiomics approaches. The results revealed the pivotal role of AraR in acid tolerance and carbohydrate utilization (including arabinose, glucose, fructose, ribose, mannose, and trehalose). RNA sequencing revealed 40 acid-responsive targets that were enriched in pathways related to pentose/glucuronate interconversions and amino sugar and nucleotide sugar metabolism. A genome-wide binding analysis via DAP-seq identified 1,279 interaction sites; the results highlighted the most significantly enriched motif, “ARCCMATMAHC”. These findings suggest that AraR plays a crucial role in regulating sugar metabolism and acid adaptation, offering mechanistic insights into microbial stress responses and providing a valuable method for addressing inhibitory processes of carbohydrate utilization under high-acid conditions.","PeriodicalId":521283,"journal":{"name":"Preprints.org","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.preprints.org/frontend/manuscript/7cc5698ff81bfd3bee0d9edcb454b6a3/download_pub","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147918068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial Engineering: The Design Era of Oncology","authors":"Eduard Porta‐Pardo","doi":"10.20944/preprints202511.1782.v1","DOIUrl":"https://doi.org/10.20944/preprints202511.1782.v1","url":null,"abstract":"Precision oncology has progressed through three eras: the genomic era, which identified mutations and molecular circuits; the archetype era, which revealed recurring tumor ecosystems; and now the emerging engineering era, enabled by AI and spatial modeling, which allows the rational reprogramming of tissue architecture. We define Spatial Engineering as a framework that integrates cellular composition, topology, physical context, and clonality into a multidimensional control space, describing how architecture can be perturbed to destabilize malignancy or restore homeostasis. Many breakthrough therapies, including checkpoint inhibitors, anti-angiogenics, CAR-T cells, and bispecific antibodies, already act through spatial mechanisms, yet most were discovered empirically. Spatial Engineering reframes them within a predictive logic of tissue design: measure architecture, model stability, intervene with intent, and adapt in real time. Early clinical trials are beginning to use spatial archetypes to assign therapy; the next leap is AI-guided simulation of drug sequences and therapeutic windows to steer malignant equilibria toward collapse. Together, these advances complete oncology’s transition from mapping tumors to designing their cure.","PeriodicalId":521283,"journal":{"name":"Preprints.org","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.preprints.org/frontend/manuscript/b62fd3cd5a358b082bffaf41ca14daad/download_pub","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147889978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}