Pathol Res Pract. 2024 Dec 21;266:155776. doi: 10.1016/j.prp.2024.155776. Online ahead of print.

ABSTRACT

Pseudomyxoma peritonei (PMP) is a rare disease caused by mucin-producing tumors that develop most frequently from the appendix. The disease is characterized by the accumulation of mucin in the abdominal cavity. Although frequent mutations in the KRAS and GNAS genes have been reported in PMP, gene expression profiles of the tumors remain to be fully clarified because of its rarity and the difficulties in collecting pure cancerous cells scattered within the mucin. To disclose the molecular features of PMP cells, we performed RNA-seq analysis of ten PMPs and their matched non-tumorous colonic epithelium in combination with laser-microdissection. As a result, we identified a total of 32 differently expressed genes (DEGs) between the tumors and non-tumorous colonic epithelium. A cell-of-origin subtype analysis with the nearest template prediction algorithm corroborated that PMP tumor cells belonged to the goblet cell subtype, and tumorous cells of PMP appear to arise from goblet cells. Interestingly, over representation analysis (ORA) uncovered that the tumors were significantly associated with three ontology terms, namely epithelial mesenchymal transition (EMT), angiogenesis, and inflammatory response. Comparison of gene expression profiles between disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous adenocarcinomas (PMCA) identified a total of 687 DEGs. Additional gene set enrichment analysis (GSEA) revealed that ontology terms "G2M checkpoint" and "E2F targets" were significantly enriched in PMCA supporting the view that PMCA has more aggressive properties than DPAM. These data may be useful to further understand the molecular characteristics of PMP.

PMID:39742833 | DOI:10.1016/j.prp.2024.155776

Biochem Biophys Res Commun. 2024 Dec 24;746:151240. doi: 10.1016/j.bbrc.2024.151240. Online ahead of print.

ABSTRACT

Utilizing Artificial Intelligence (AI) in computational biology techniques could offer significant advantages in alleviating the growing workloads faced by structural biologists, especially with the emergence of big data. In this study, we employed Delaunay tessellation as a promising method to obtain the overall structural topology of proteins. Subsequently, we developed multi-class deep neural network models to classify protein superfamilies based on their local topology. Our models achieved a test accuracy of approximately 0.92 in classifying proteins into 18 well-populated superfamilies. We believe that the results of this study hold substantial value since, to the best of our knowledge, no previous studies have reported the utilization of protein topological data for protein classification through deep learning and Delaunay tessellation.

PMID:39742787 | DOI:10.1016/j.bbrc.2024.151240

Sci Adv. 2025 Jan 3;11(1):eado6894. doi: 10.1126/sciadv.ado6894. Epub 2025 Jan 1.

ABSTRACT

The early detection of neurodegenerative diseases necessitates the identification of specific brain-derived biomolecules in peripheral blood. In this context, our investigation delineates the role of amyloid precursor-like protein 1 (APLP1)-a protein predominantly localized in oligodendrocytes and neurons-as a previously unidentified biomarker in extracellular vesicles (EVs). Through rigorous analysis, APLP1+ EVs from human sera were unequivocally determined to be of cerebral origin. This assertion was corroborated by distinctive small RNA expression patterns of APLP1+ EVs. The miRNAs' putative targets within these EVs manifested pronounced expression in the brain, fortifying their neurospecific provenance. We subjected our findings to stringent validation using Thy-1 GFP M line mice, transgenic models wherein GFP expression is confined to hippocampal neurons. An amalgamation of these results with an exhaustive data analysis accentuates the potential of APLP1+ EVs as cerebrally originated biomarkers. Synthesizing our findings, APLP1+ EVs are postulated not merely as diagnostic markers but as seminal entities shaping the future trajectory of neurodegenerative disease diagnostics.

PMID:39742488 | DOI:10.1126/sciadv.ado6894

Imeta. 2024 Dec 15;3(6):e251. doi: 10.1002/imt2.251. eCollection 2024 Dec.

ABSTRACT

The iMeta Conference 2024 provides a platform to promote the development of an innovative scientific research ecosystem for microbiome and One Health. The four key components - Technology, Research (Biology), Academic journals, and Social media - form a synergistic ecosystem. Advanced technologies drive biological research, which generates novel insights that are disseminated through academic journals. Social media plays a crucial role in engaging the public and facilitating scientific communication, thus amplifying the impact of research. Together, these elements create a self-sustaining loop that fosters continuous innovation and collaboration in the field of bioinformatics, biotechnology and microbiome research.

PMID:39742310 | PMC:PMC11683455 | DOI:10.1002/imt2.251

Imeta. 2024 Dec 20;3(6):e260. doi: 10.1002/imt2.260. eCollection 2024 Dec.

ABSTRACT

Phosphorus, as a nonrenewable resource, plays a crucial role in crop development and productivity. However, the extent to which straw amendments contribute to the dynamics of soil alkaline phosphomonoesterase (ALP)-producing bacterial community and functionality over an extended period remains elusive. Here, we conducted a 7-year long-term field experiment consisting of a no-fertilizer control, a chemical fertilizer treatment, and three straw (straw, straw combined with manure, and straw biochar) treatments. Our results indicated that straw amendments significantly improved the succession patterns of the ALP-producing bacterial diversity. Simultaneously, straw amendments significantly increased the network stability of the ALP-producing bacteria over time, as evidenced by higher network robustness, a higher ratio of negative to positive cohesion, and lower network vulnerability. High dynamic and stability of ALP-producing bacterial community generated high ALP activity which further increased soil Phosphorus (P) availability as well as maize productivity.

PMID:39742308 | PMC:PMC11683463 | DOI:10.1002/imt2.260

Front Immunol. 2024 Dec 17;15:1521629. doi: 10.3389/fimmu.2024.1521629. eCollection 2024.

ABSTRACT

BACKGROUND: Progestin And AdipoQ Receptor Family Member VI (PAQR6) plays a significant role in the non-genomic effects of rapid steroid responses and is abnormally expressed in various tumors. However, its biological function in kidney renal clear cell carcinoma (KIRC) and its potential as a therapeutic target remain underexplored.

METHODS: In this study, PAQR6 was identified as a critical oncogene by WGCNA algorithm and differential gene expression analysis using TCGA - KIRC and GSE15641 data. The differences in PAQR6 expression and its association with KIRC survival outcomes were investigated, and transcriptomic data were used to further elucidate PAQR6's biological functions. Moreover, XCELL and single - cell analysis assessed the correlation between PAQR6 expression and immune infiltration. TIDE algorithm was used to assess how well various patient cohorts responded to immune checkpoint therapy. Finally, the role of PAQR6 in the development of KIRC was verified through EdU, scratch assays, and Transwell assays.

RESULTS: Our findings suggest that elevated expression of PAQR6 is linked to a poor prognosis for KIRC patients. Functional enrichment analysis demonstrated that PAQR6 is primarily involved in angiogenesis and pluripotent stem cell differentiation, which are crucial in mediating the development of KIRC. Additionally, we established a ceRNA network that is directly related to overall prognosis, further supporting the role of PAQR6 as a prognostic biomarker for KIRC.

CONCLUSION: Using both computational and experimental methods, this study leads the charge in discovering and verifying PAQR6 as a prognostic biomarker and possible therapeutic target for KIRC. In the future, to determine its molecular mechanism in KIRC carcinogenesis, more in vivo research will be carried out.

PMID:39742277 | PMC:PMC11685228 | DOI:10.3389/fimmu.2024.1521629

Breast Cancer Res. 2024 Dec 31;26(1):192. doi: 10.1186/s13058-024-01931-5.

ABSTRACT

BACKGROUND: Primary luminal breast cancer cells lose their identity rapidly in standard tissue culture, which is problematic for testing hormone interventions and molecular pathways specific to the luminal subtype. Breast cancer organoids are thought to retain tumor characteristics better, but long-term viability of luminal-subtype cases is a persistent challenge. Our goal was to adapt short-term organoids of luminal breast cancer for parallel testing of genetic and pharmacologic perturbations.

METHODS: We freshly isolated patient-derived cells from luminal tumor scrapes, miniaturized the organoid format into 5 µl replicates for increased throughput, and set an endpoint of 14 days to minimize drift. Therapeutic hormone targeting was mimicked in these "zero-passage" organoids by withdrawing β-estradiol and adding 4-hydroxytamoxifen. We also examined sulforaphane as an electrophilic stress and commercial nutraceutical with reported anti-cancer properties. Downstream mechanisms were tested genetically by lentiviral transduction of two complementary sgRNAs and Cas9 stabilization for the first week of organoid culture. Transcriptional changes were measured by RT-qPCR or RNA sequencing (RNA-seq), and organoid phenotypes were quantified by serial brightfield imaging, digital image segmentation, and regression modeling of volumetric growth rates.

RESULTS: We achieved > 50% success in initiating luminal breast cancer organoids from tumor scrapes and maintaining them to the 14-day zero-passage endpoint. Success was mostly independent of clinical parameters, supporting general applicability of the approach. Abundance of ESR1 and PGR in zero-passage organoids consistently remained within the range of patient variability at the endpoint. However, responsiveness to hormone withdrawal and blockade was highly variable among luminal breast cancer cases tested. Combining sulforaphane with knockout of NQO1 (a phase II antioxidant response gene and downstream effector of sulforaphane) also yielded a breadth of organoid growth phenotypes, including growth inhibition with sulforaphane, growth promotion with NQO1 knockout, and growth antagonism when combined.

CONCLUSIONS: Zero-passage organoids are a rapid and scalable way to interrogate properties of luminal breast cancer cells from patient-derived material. This includes testing drug mechanisms of action in different clinical cohorts. A future goal is to relate inter-patient variability of zero-passage organoids to long-term outcomes.

PMID:39741344 | DOI:10.1186/s13058-024-01931-5

J Transl Med. 2024 Dec 31;22(1):1160. doi: 10.1186/s12967-024-05979-x.

ABSTRACT

Cardiovascular diseases (CVDs) are the leading cause of mortality among individuals with noncommunicable diseases worldwide. Obesity is associated with an increased risk of developing cardiovascular disease (CVD). Mitochondria are integral to the cardiovascular system, and it has been reported that mitochondrial transfer is associated with the pathogenesis of multiple CVDs and obesity. This review offers a comprehensive examination of the relevance of mitochondrial transfer to cardiovascular health and disease, emphasizing the critical functions of mitochondria in energy metabolism and signal transduction within the cardiovascular system. This highlights how disruptions in mitochondrial transfer contribute to various CVDs, such as myocardial infarction, cardiomyopathies, and hypertension. Additionally, we provide an overview of the molecular mechanisms governing mitochondrial transfer and its potential implications for CVD treatment. This finding underscores the therapeutic potential of mitochondrial transfer and addresses the various mechanisms and challenges in its implementation. By delving into mitochondrial transfer and its targeted modulation, this review aims to advance our understanding of cardiovascular disease treatment, presenting new insights and potential therapeutic strategies in this evolving field.

PMID:39741312 | DOI:10.1186/s12967-024-05979-x

Sci Rep. 2024 Dec 31;14(1):32174. doi: 10.1038/s41598-024-84276-5.

ABSTRACT

The heparan sulfate (HS)-rich extracellular matrix (ECM) serves as an initial interaction site for the homotrimeric spike (S) protein of SARS-CoV-2 to facilitate subsequent docking to angiotensin-converting enzyme 2 (ACE2) receptors and cellular infection. More recent variants, notably Omicron, have evolved by swapping several amino acids to positively charged residues to enhance the interaction of the S-protein trimer with the negatively charged HS. However, these enhanced interactions may reduce Omicron's ability to move through the HS-rich ECM to effectively find ACE2 receptors and infect cells, raising the question of how to mechanistically explain HS-associated viral movement. In this work, we show that Omicron S proteins have evolved to balance HS interaction stability and dynamics, resulting in enhanced mobility on an HS-functionalized artificial matrix. This property is achieved by the ability of Omicron S-proteins to cross-link at least two HS chains, allowing direct S-protein switching between chains as a prerequisite for cell surface mobility. Optimized HS interactions can be targeted pharmaceutically, as an HS mimetic significantly suppressed surface binding and cellular infection specifically of the Omicron variant. These findings suggest a robust way to interfere with SARS-CoV-2 Omicron infection and potentially future variants.

PMID:39741163 | DOI:10.1038/s41598-024-84276-5

NPJ Syst Biol Appl. 2024 Dec 31;10(1):151. doi: 10.1038/s41540-024-00477-8.

ABSTRACT

Multicellularity is one of the major evolutionary transitions, and its rise provided the ingredients for the emergence of a biosphere inhabited by complex organisms. Over the last decades, the potential for bioengineering multicellular systems has been instrumental in interrogating nature and exploring novel paths to regeneration, disease, cognition, and behaviour. Here, we provide a list of open problems that encapsulate many of the ongoing and future challenges in the field and suggest conceptual approaches that may facilitate progress.

PMID:39741147 | DOI:10.1038/s41540-024-00477-8

Life Sci Alliance. 2024 Dec 31;8(3):e202403007. doi: 10.26508/lsa.202403007. Print 2025 Mar.

ABSTRACT

Large multiprotein machines are central to many biological processes. However, stoichiometric determination of protein complex subunits in their native states presents a significant challenge. This study addresses the limitations of current tools in accuracy and precision by introducing concatemer-assisted stoichiometry analysis (CASA). CASA leverages stable isotope-labeled concatemers and liquid chromatography-parallel reaction monitoring-mass spectrometry (LC-PRM-MS) to achieve robust quantification of proteins with sub-femtomole sensitivity. As a proof of concept, CASA was applied to study budding yeast kinetochores. Stoichiometries were determined for ex vivo reconstituted kinetochore components, including the canonical H3 nucleosomes, centromeric (Cse4CENP-A) nucleosomes, centromere proximal factors (Cbf1 and CBF3 complex), inner kinetochore proteins (Mif2CENP-C, Ctf19CCAN complex), and outer kinetochore proteins (KMN network). Absolute quantification by CASA revealed Cse4CENP-A as a cell cycle-controlled limiting factor for kinetochore assembly. These findings demonstrate that CASA is applicable for stoichiometry analysis of multiprotein assemblies.

PMID:39741008 | DOI:10.26508/lsa.202403007

Biochem Biophys Res Commun. 2024 Dec 28;745:151262. doi: 10.1016/j.bbrc.2024.151262. Online ahead of print.

ABSTRACT

The root epidermis of Arabidopsis (Arabidopsis thaliana) consists of two distinct cell types: hair (H) cells and non-hair (N) cells, whose patterning is regulated by a network of genes. Among these, the WEREWOLF (WER) gene, encoding an R2R3 MYB transcription factor, acts as a master regulator by promoting the expression of key downstream genes, such as GLABRA2 and CAPRICE. However, the mechanisms controlling WER expression have remained largely unexplored. In this study, we analyzed WER promoter to identify putative cis-regulatory elements that govern its N-position-preferential expression. We generated a series of WER promoter constructs with progressive 5' truncations, internal deletions/substitutions, and synthetic 18x tandem repeats of core elements, each driving expression of a β-glucuronidase (GUS) reporter gene in the presence of the nos terminator. We discovered that the region between -420 and -346 bp was required for the N-position-preferential expression. When synthetic 18x core elements from this region were used to drive GUS expression with WER terminator, the -420 to -391 bp and -390 to -361 bp cores showed weak N-position expression in the root epidermis, while the -375 to -346 bp core displayed moderate N-position expression. Additionally, WER expression driven by the -420 to -391 bp, -390 to -361 bp, and -375 to -346 bp 18x cores successfully complemented the wer mutant phenotype. These findings suggest that the cis-regulatory elements responsible for N-position-preferential expression are dispersed across the WER promoter, and the -375 to -346 bp region plays a major role in driving N-position-preferential expression. In addition, our results indicate that WER terminator is required for the proper functioning of these cis-regulatory elements.

PMID:39740398 | DOI:10.1016/j.bbrc.2024.151262

Proteomics. 2024 Dec 30:e202400279. doi: 10.1002/pmic.202400279. Online ahead of print.

ABSTRACT

Naturally occurring fragments of collagen type I alpha 1 chain (COL1A1) have been previously associated with chronic kidney disease (CKD), with some fragments showing positive and others negative associations. Using urinary peptidome data from healthy individuals (n = 1131) and CKD patients (n = 5585) this aspect was investigated in detail. Based on the hypothesis that many collagen peptides are derived not from the full, mature collagen molecule, but from (larger) collagen degradation products, relationships between COL1A1 peptides containing identical sequences were investigated, with the smaller (offspring) peptide being a possible degradation product of the larger (parent) one. The strongest correlations were found for relationships where the parent differed by a maximum of three amino acids from the offspring, indicating an exopeptidase-regulated stepwise degradation process. Regression analysis indicated that CKD affects this degradation process. A comparison of matched CKD patients and control individuals (n = 612 each) showed that peptides at the start of the degradation process were consistently downregulated in CKD, indicating an attenuation of COL1A1 endopeptidase-mediated degradation. However, as these peptides undergo further degradation, likely mediated by exopeptidases, this downregulation can become less significant or even reverse, leading to an upregulation of later-stage fragments and potentially explaining the inconsistencies observed in previous studies.

PMID:39740102 | DOI:10.1002/pmic.202400279

Nucleic Acids Res. 2024 Dec 31:gkae1273. doi: 10.1093/nar/gkae1273. Online ahead of print.

ABSTRACT

The eukaryotic microrchidia (MORC) protein family are DNA gyrase, Hsp90, histidine kinase, MutL (GHKL)-type ATPases involved in gene expression regulation and chromatin compaction. The molecular mechanisms underlying these activities are incompletely understood. Here, we studied the full-length human MORC2 protein biochemically. We identified a DNA binding site in the C-terminus of the protein, and we observe that this region can be phosphorylated in cells. DNA binding by MORC2 reduces its ATPase activity and MORC2 can entrap multiple DNA substrates between its N-terminal GHKL and C-terminal coiled coil 3 dimerization domains. Finally, we observe that the MORC2 C-terminal DNA binding region is required for gene silencing in cells. Together, our data provide a model to understand how MORC2 engages with DNA substrates to mediate gene silencing.

PMID:39739841 | DOI:10.1093/nar/gkae1273

Pharmacol Res Perspect. 2025 Feb;13(1):e70014. doi: 10.1002/prp2.70014.

ABSTRACT

Mathematical models of thrombin generation (TG) that have been developed are based on a systems biology approach. Although this approach provides important information about the coagulation system, its clinical applicability is limited by its complexity and number of input variables required. The aim of this study was to develop a semimechanistic model able to describe TG in trauma and control patients. A dataset containing longitudinal data of TG assays and coagulation factors from 40 trauma patients and 20 control patients was used for model building. The model considered three fundamental processes: the degradation of tissue factor (TF) through a first-order process, the activation of factor II by the TF through a first-order process, and the degradation of thrombin through a first-order process. Model fitting was performed using a nonlinear mixed-effects approach. The condition of the patient (trauma and control) and coagulation factors were modelled as covariates. Model building demonstrated the presence of two additional processes that improved the predictive capacity of the model: the activation of factor II by TF governed by a second-order constant and, a mechanism of factor II activation by TF characterized by a 7-compartment transit chain governed by a second-order constant. In the covariate model only the inclusion of patient condition was significant. Model evaluation demonstrated excellent performance in describing the temporal pattern of TG in trauma and control patients. Thrombin generation can be adequately modelled using a semimechanistic approach. Its application in practice could help to better assess the risk of hemorrhage and/or thrombosis in different settings.

PMID:39739766 | DOI:10.1002/prp2.70014

PLoS One. 2024 Dec 31;19(12):e0315510. doi: 10.1371/journal.pone.0315510. eCollection 2024.

ABSTRACT

Gap junction intercellular communication (GJIC) between two adjacent cells involves direct exchange of cytosolic ions and small molecules via connexin gap junction channels (GJCs). Connexin GJCs have emerged as drug targets, with small molecule connexin inhibitors considered a viable therapeutic strategy in several diseases. The molecular mechanisms of GJC inhibition by known small molecule connexin inhibitors remain unknown, preventing the development of more potent and connexin-specific therapeutics. Here we show that two GJC inhibitors, mefloquine (MFQ) and 2-aminoethoxydiphenyl borate (2APB) bind to Cx32 and block dye permeation across Cx32 hemichannels (HCs) and GJCs. Cryo-EM analysis shows that 2APB binds to "site A", close to the N-terminal gating helix of Cx32 GJC, restricting the entrance to the channel pore. In contrast, MFQ binds to a distinct "site M", deeply buried within the pore. MFQ binding to this site modifies the electrostatic properties of Cx32 pore. Mutagenesis of V37, a key residue located in the site M, renders Cx32 HCs and GJCs insensitive to MFQ-mediated inhibition. Moreover, our cryo-EM analysis, mutagenesis and activity assays show that MFQ targets the M site in Cx43 GJC similarly to Cx32. Taken together, our results point to a conserved inhibitor binding site in connexin channels, opening a new route for development of specific drugs targeting connexins.

PMID:39739741 | DOI:10.1371/journal.pone.0315510

Adv Sci (Weinh). 2024 Dec 30:e2414278. doi: 10.1002/advs.202414278. Online ahead of print.

ABSTRACT

Regulation of the immune response is key to promoting bone regeneration by electroactive biomaterials. However, how electrical signals at the micro- and nanoscale regulate the immune response and subsequent angiogenesis during bone regeneration remains to be elucidated. Here, the distinctly different surface potential distributions on charged poly(vinylidene fluoridetrifluoroethylene) (P(VDF-TrFE)) matrix surfaces are established by altering the dimensions of ferroelectric nanofillers from 0D BaTiO3 nanoparticles (homogeneous surface potential distribution, HOPD) to 1D BaTiO3 nanofibers (heterogeneous surface potential distribution, HEPD). Compared to HOPD, HEPD is significantly better at inducing the M2 polarization of macrophages and promoting neovascularization, which results in accelerated bone regeneration in vivo. The transcriptomic analysis reveals that macrophages modulated by HEPD display high expression levels of pro-angiogenic genes, which is corroborated by tube-formation assays, RT-qPCR, and western blot analyses in vitro. Mechanistic explorations elucidate activation of the PI3K-Akt signaling pathway, which in turn induces the polarization of macrophages toward a pro-angiogenic phenotype. This study elucidates the cascade of biological processes by which heterogeneous electrical signals at the micro- and nanoscale modulate macrophage functions to promote vascularization and bone regeneration. Hence, this study provides new insights into how the micro- and nanoscale distribution characteristics of electrical signals facilitate bone regeneration.

PMID:39739591 | DOI:10.1002/advs.202414278

Handb Exp Pharmacol. 2024 Dec 31. doi: 10.1007/164_2024_733. Online ahead of print.

ABSTRACT

Quantitative systems pharmacology (QSP) is a modeling approach employed in drug research and development that combines mechanistic representations of biological processes with drug pharmacology to deepen biological understanding and predict the responses to novel drugs or protocols. QSP has evolved from and is related to other modeling approaches, but has a number of unique attributes and applications. Here, we clarify the definition of QSP and its key features, trace its evolution, briefly compare it to other approaches, and explain why and how it can be used to reduce risk and improve efficiency in drug research and development.

PMID:39739036 | DOI:10.1007/164_2024_733

Nat Struct Mol Biol. 2024 Dec 30. doi: 10.1038/s41594-024-01460-x. Online ahead of print.

NO ABSTRACT

PMID:39738853 | DOI:10.1038/s41594-024-01460-x

J Mol Med (Berl). 2024 Dec 30. doi: 10.1007/s00109-024-02512-x. Online ahead of print.

ABSTRACT

Gaucher disease (GD), an autosomal recessive lysosomal disorder, primarily affects the lysosomal enzyme β-glucocerebrosidase (GCase), leading to glucosylceramide accumulation in lysosomes. GD presents a wide spectrum of clinical manifestations. This study deploys immune-based proteomics and mass spectrometry-based metabolomics technologies to comprehensively investigate the biochemical landscape in 43 deeply phenotyped type 1 GD patients compared to 59 controls. Conventional and systems biology approaches have been used to analyze the data. The results show promising biological imprints. Elevated phosphatidylcholines in GD patients suggest altered lipid metabolism, potentially due to their increased synthesis. This points to endoplasmic reticulum stress and impaired lipid trafficking, commonly seen in lysosomal diseases. GD patients exhibit an inflammatory profile with elevated cytokines and autoimmune-like inflammation, even in treated patients, highlighting the complexity of GD-related immune imbalances. Mitochondrial dysfunction clues are found through increased oxidative stress markers and altered acylcarnitine profiles in GD patients, suggesting mitochondrial membrane dysfunction affecting carnitine-carrying capacity. Furthermore, platelet count, splenectomy, treatment, and clinical traits were associated with specific omics features, providing insights into GD's clinical heterogeneity and potential diagnostic markers. Autophagy inhibition appears pivotal in GD, driving lipid synthesis, impaired mitochondrial function, and inflammation through chronic activation of mTORC1. Despite limitations like focusing on type 1 GD and using targeted omics approaches, this study provides valuable insights into GD metabolic and immune dysregulation. It lays the basis for future comprehensive investigations into GD manifestations with broader scope and molecular coverage. KEY MESSAGES: The study sheds light on metabolic and immune dysregulation in Gaucher disease. Gaucher disease patients showed elevated phosphatidylcholines, disrupted lipid metabolism, and inflammation profiles. Signs of mitochondrial dysfunction are evident in Gaucher disease patients, with autophagy inhibition significantly affecting lipid synthesis, mitochondrial function, and inflammation via chronic activation of mTORC1.

PMID:39738845 | DOI:10.1007/s00109-024-02512-x