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Reversing CD8A + T cell deficiency by methionine metabolism intervention enhancing immunotherapy response in MTAP-deleted osteosarcoma (A) Flowchart depicting methionine restriction diet combined with immune checkpoint therapy. (B and C) In vivo orthotopic tibia models of DuNN shMtap in C3H mice, depicting tumor growth curves (mean ± SD) and tumor weights at experimental endpoints, treated by methionine restriction diet combined with immune checkpoint therapy. ND n = 8; ICT n = 8; MR n = 8; Combined n = 8. Statistical analyses were performed using two-tailed Student’s t tests. (D) Metabolomics of the intestines in DuNN shMtap tumor-bearing C3H mice revealed downregulation of methionine-related metabolites following dietary methionine restriction. (E) Pathological characteristics and immunohistochemistry (CD8A) of tumor tissues from DuNN shMtap in C3H mice, treated by methionine restriction diet combined with immune checkpoint therapy. Arrows indicate T cells. Scale bar, 100 μm (F) Flowchart depicting <t>MAT2A</t> inhibition combined with immune checkpoint therapy. (G and H) In vivo orthotopic tibia models of DuNN shMtap in C3H mice, depicting tumor growth curves (mean ± SD) and survival curve at experimental endpoints, treated by MAT2A inhibition combined with immune checkpoint therapy. ND n = 6; ICT n = 6; MR n = 6; Combined n = 6. Statistical analyses were performed using two-tailed Student’s t tests. (I) Pathological characteristics and immunohistochemistry (CD8A, CD4, and FOXP3) of tumor tissues from DuNN shMtap in C3H mice, treated by MAT2A inhibition combined with immune checkpoint therapy. Arrows indicate T cells. Scale bar, 100 μm.

Mat2a Protein, supplied by Pharmaron Inc, used in various techniques. Bioz Stars score: 90/100, based on 1 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
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1) Product Images from "Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma"

Article Title: Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma

Journal: Cell Reports Medicine

doi: 10.1016/j.xcrm.2025.101977

Figure Legend Snippet: Reversing CD8A + T cell deficiency by methionine metabolism intervention enhancing immunotherapy response in MTAP-deleted osteosarcoma (A) Flowchart depicting methionine restriction diet combined with immune checkpoint therapy. (B and C) In vivo orthotopic tibia models of DuNN shMtap in C3H mice, depicting tumor growth curves (mean ± SD) and tumor weights at experimental endpoints, treated by methionine restriction diet combined with immune checkpoint therapy. ND n = 8; ICT n = 8; MR n = 8; Combined n = 8. Statistical analyses were performed using two-tailed Student’s t tests. (D) Metabolomics of the intestines in DuNN shMtap tumor-bearing C3H mice revealed downregulation of methionine-related metabolites following dietary methionine restriction. (E) Pathological characteristics and immunohistochemistry (CD8A) of tumor tissues from DuNN shMtap in C3H mice, treated by methionine restriction diet combined with immune checkpoint therapy. Arrows indicate T cells. Scale bar, 100 μm (F) Flowchart depicting MAT2A inhibition combined with immune checkpoint therapy. (G and H) In vivo orthotopic tibia models of DuNN shMtap in C3H mice, depicting tumor growth curves (mean ± SD) and survival curve at experimental endpoints, treated by MAT2A inhibition combined with immune checkpoint therapy. ND n = 6; ICT n = 6; MR n = 6; Combined n = 6. Statistical analyses were performed using two-tailed Student’s t tests. (I) Pathological characteristics and immunohistochemistry (CD8A, CD4, and FOXP3) of tumor tissues from DuNN shMtap in C3H mice, treated by MAT2A inhibition combined with immune checkpoint therapy. Arrows indicate T cells. Scale bar, 100 μm.

Techniques Used: In Vivo, Two Tailed Test, Immunohistochemistry, Inhibition

MAT2A inhibition triggering IKZF1-mediated PD-L1 expression in MTAP-deleted osteosarcoma (A, B, and C) Integrated analysis of transcription factors associated with PD-L1 expression in SGH-OS and TARGET-OS and genes upregulated by treating with MAT2A inhibitor rather than immune checkpoint therapy. Spearman correlation tests were performed, and data with p values < 0.05 were considered statistically significant. (D and E) Protein expression of MAT2A and PD-L1 in MTAP-deleted OS cells (143B) treated with MAT2A inhibitor PF-9366, and protein expression of IKZF1, MAT2A, and PD-L1 in 143B cells co-treated with siIKZF1, assessed by western blotting. (F) IKZF1 RNA expression in wild-type (WT) ( n = 36) and MTAP-deleted (DEL) ( n = 14) cases in SGH-OS cohort. Statistical analyses were performed using two-tailed Student’s t tests. (G) Transcriptomic pathway analysis of cells by treating with PF-9366, using GSEA analysis ( p value < 0.05) on Hallmark gene sets. ES refers to enrichment score, and NES refers to normalized enrichment score. (H and I) Survival curve of TARGET-OS and TCGA-SARC related with IKZF1 expression. Statistical significance was calculated using the log rank test. (J) Summary schematic illustrating the mechanism of methionine intervention enhancing immune checkpoint therapy in MTAP-deleted osteosarcoma (MTAP-del OS).

Figure Legend Snippet: MAT2A inhibition triggering IKZF1-mediated PD-L1 expression in MTAP-deleted osteosarcoma (A, B, and C) Integrated analysis of transcription factors associated with PD-L1 expression in SGH-OS and TARGET-OS and genes upregulated by treating with MAT2A inhibitor rather than immune checkpoint therapy. Spearman correlation tests were performed, and data with p values < 0.05 were considered statistically significant. (D and E) Protein expression of MAT2A and PD-L1 in MTAP-deleted OS cells (143B) treated with MAT2A inhibitor PF-9366, and protein expression of IKZF1, MAT2A, and PD-L1 in 143B cells co-treated with siIKZF1, assessed by western blotting. (F) IKZF1 RNA expression in wild-type (WT) ( n = 36) and MTAP-deleted (DEL) ( n = 14) cases in SGH-OS cohort. Statistical analyses were performed using two-tailed Student’s t tests. (G) Transcriptomic pathway analysis of cells by treating with PF-9366, using GSEA analysis ( p value < 0.05) on Hallmark gene sets. ES refers to enrichment score, and NES refers to normalized enrichment score. (H and I) Survival curve of TARGET-OS and TCGA-SARC related with IKZF1 expression. Statistical significance was calculated using the log rank test. (J) Summary schematic illustrating the mechanism of methionine intervention enhancing immune checkpoint therapy in MTAP-deleted osteosarcoma (MTAP-del OS).

Techniques Used: Inhibition, Expressing, Western Blot, RNA Expression, Two Tailed Test

Figure Legend Snippet:

Techniques Used: Control, Recombinant, Saline, Red Blood Cell Lysis, Lysis, Staining, Screening Assay, Transfection, Plasmid Preparation, In Vitro, CCK-8 Assay, Cell Isolation, Gene Expression, Sequencing, Methylation, In Vivo, Software, Microscopy, Refractive Index, Mass Spectrometry

Image Search Results

A Score plot depicting the separation of metabolic gene patterns in the human DW and NDW groups through PCA analysis in GSE154556 . B Volcano plot showing the differentially expressed metabolic genes between human DWs and NDWs in GSE154556 . Differentially expressed genes were assessed with the limma moderated two-sided t test. C KEGG analysis of typical differential metabolic pathways between human DWs and NDWs in GSE154556 . D t-SNE plots of the characterized cell clusters identified via scRNA-seq of human wound samples ( GSE165816 ). E Venn diagram showing the shared altered metabolic differential genes and their origins. F Correlation analysis of the expression levels of the metabolic candidates and the inflammatory macrophage infiltration score in GSE154556 . The text annotations above showed the cellular origins of the main differences of these candidates analyzed from GSE165816 . G Cellular communication analysis revealing potential interactions among pericytes with low MAT2A expression and other cell types from GSE165816 . H Schematic illustration of the methionine cycle, and the relative levels of methionine in the human DW and NDW groups. n = 12 biologically independent samples. I Expression levels of metabolic enzymes involved in the methionine cycle in the two groups ( GSE165816 ). Non-parametric two-sided Wilcoxon rank-sum test was used. J Immunofluorescence staining and statistical analysis demonstrating the expression levels of MAT2A in CD31-NG2+PDGFRβ+ pericytes from human wounds. n = 3 biologically independent samples. K Pericytes were classified into samples with high MAT2A expression levels and samples with low MAT2A expression levels ( GSE165816 ); grouped samples were analyzed via GSEA. The median expression of the gene was used as the dividing line. Data were shown as mean ± SD. Statistical significance was determined using hypergeometric test ( C ) and two-tailed unpaired t test ( H , J ). Source data are provided as a Source Data file.

Journal: Nature Communications

Article Title: A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models

doi: 10.1038/s41467-025-65659-2

Figure Lengend Snippet: A Score plot depicting the separation of metabolic gene patterns in the human DW and NDW groups through PCA analysis in GSE154556 . B Volcano plot showing the differentially expressed metabolic genes between human DWs and NDWs in GSE154556 . Differentially expressed genes were assessed with the limma moderated two-sided t test. C KEGG analysis of typical differential metabolic pathways between human DWs and NDWs in GSE154556 . D t-SNE plots of the characterized cell clusters identified via scRNA-seq of human wound samples ( GSE165816 ). E Venn diagram showing the shared altered metabolic differential genes and their origins. F Correlation analysis of the expression levels of the metabolic candidates and the inflammatory macrophage infiltration score in GSE154556 . The text annotations above showed the cellular origins of the main differences of these candidates analyzed from GSE165816 . G Cellular communication analysis revealing potential interactions among pericytes with low MAT2A expression and other cell types from GSE165816 . H Schematic illustration of the methionine cycle, and the relative levels of methionine in the human DW and NDW groups. n = 12 biologically independent samples. I Expression levels of metabolic enzymes involved in the methionine cycle in the two groups ( GSE165816 ). Non-parametric two-sided Wilcoxon rank-sum test was used. J Immunofluorescence staining and statistical analysis demonstrating the expression levels of MAT2A in CD31-NG2+PDGFRβ+ pericytes from human wounds. n = 3 biologically independent samples. K Pericytes were classified into samples with high MAT2A expression levels and samples with low MAT2A expression levels ( GSE165816 ); grouped samples were analyzed via GSEA. The median expression of the gene was used as the dividing line. Data were shown as mean ± SD. Statistical significance was determined using hypergeometric test ( C ) and two-tailed unpaired t test ( H , J ). Source data are provided as a Source Data file.

Article Snippet: D OCR measurement in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ (TargetMol, USA, T2796) restoration.

Techniques: Expressing, Immunofluorescence, Staining, Two Tailed Test

A ScRNA-seq profiling workflow created with BioRender.com. B Western blot analysis of MAT2A expression in pericytes isolated from the indicated mouse skin. C Representative images of cutaneous wounds of mice on days 0, 4, 8, 12, and 16 after wound model generation by surgical excision. Ratio of wound sizes were quantified by using ImageJ software and were calculated by the percentages of wound closure compared to day 0 wound size. n = 3 mice for sampling at the indicated time points. D Representative blood perfusion images and statistical analysis of wounds at days 4 and 8 after surgery. E Cutaneous wound sections were subjected to H&E and Masson’s trichrome staining, and IHC staining for Ki-67, α-SMA, and IL6 were performed. Samples were collected at day 8 after wound model generation. n = 3 mice for sampling at the indicated time points. Scale bar, 100 μm. F UMAP plot showing identified cell clusters of mouse skin. G Representative immunofluorescence images and statistical analysis demonstrating the pericyte abundance in cutaneous wounds on day 4. H Volcano plot showing the differential genes of pericyte clusters between the two groups based on P value < 0.05 and absolute log 2 (Fold Change) > 0.25. Non-parametric two-sided Wilcoxon rank-sum test was used. I Bar graph showing the functionally enriched pathways associated with the significantly upregulated or downregulated genes (MAT2A LOF vs. control) in the pericyte clusters. J Cellular communication analysis revealing potential interactions among pericytes and other cell types. K Violin-box plots representing the expression of proinflammatory or anti-inflammatory signature genes in the macrophage clusters. Macrophage cells in control group, n = 6201; macrophage cells in MAT2A LOF group, n = 6763. L UMAP plot and quantitative analysis showing characterized cell clusters of infiltrated macrophages and their proportions in the indicated groups. M Cell trajectory analysis of the characterized cell clusters of infiltrated macrophages. N Representative immunofluorescence images and statistical analysis demonstrating the macrophageinfiltration in cutaneous wound tissues on day 8. n = 3 mice in each group. Scale bar, 20 μm. For the box and violin-box plots in ( G ), and ( K ), the centerlines indicated the medians. The box limits indicated the first and third quartiles. The whiskers indicated the maxima and minima. Data in the bar plots were shown as mean ± SD. n = 3 biologically independent samples ( D , G ). Statistical significance was determined using two-way ANOVA with Tukey’s multiple comparisons test ( C ) and two-tailed unpaired t test ( D , G , K , N ). Source data are provided as a Source Data file.

Journal: Nature Communications

Article Title: A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models

doi: 10.1038/s41467-025-65659-2

Figure Lengend Snippet: A ScRNA-seq profiling workflow created with BioRender.com. B Western blot analysis of MAT2A expression in pericytes isolated from the indicated mouse skin. C Representative images of cutaneous wounds of mice on days 0, 4, 8, 12, and 16 after wound model generation by surgical excision. Ratio of wound sizes were quantified by using ImageJ software and were calculated by the percentages of wound closure compared to day 0 wound size. n = 3 mice for sampling at the indicated time points. D Representative blood perfusion images and statistical analysis of wounds at days 4 and 8 after surgery. E Cutaneous wound sections were subjected to H&E and Masson’s trichrome staining, and IHC staining for Ki-67, α-SMA, and IL6 were performed. Samples were collected at day 8 after wound model generation. n = 3 mice for sampling at the indicated time points. Scale bar, 100 μm. F UMAP plot showing identified cell clusters of mouse skin. G Representative immunofluorescence images and statistical analysis demonstrating the pericyte abundance in cutaneous wounds on day 4. H Volcano plot showing the differential genes of pericyte clusters between the two groups based on P value < 0.05 and absolute log 2 (Fold Change) > 0.25. Non-parametric two-sided Wilcoxon rank-sum test was used. I Bar graph showing the functionally enriched pathways associated with the significantly upregulated or downregulated genes (MAT2A LOF vs. control) in the pericyte clusters. J Cellular communication analysis revealing potential interactions among pericytes and other cell types. K Violin-box plots representing the expression of proinflammatory or anti-inflammatory signature genes in the macrophage clusters. Macrophage cells in control group, n = 6201; macrophage cells in MAT2A LOF group, n = 6763. L UMAP plot and quantitative analysis showing characterized cell clusters of infiltrated macrophages and their proportions in the indicated groups. M Cell trajectory analysis of the characterized cell clusters of infiltrated macrophages. N Representative immunofluorescence images and statistical analysis demonstrating the macrophageinfiltration in cutaneous wound tissues on day 8. n = 3 mice in each group. Scale bar, 20 μm. For the box and violin-box plots in ( G ), and ( K ), the centerlines indicated the medians. The box limits indicated the first and third quartiles. The whiskers indicated the maxima and minima. Data in the bar plots were shown as mean ± SD. n = 3 biologically independent samples ( D , G ). Statistical significance was determined using two-way ANOVA with Tukey’s multiple comparisons test ( C ) and two-tailed unpaired t test ( D , G , K , N ). Source data are provided as a Source Data file.

Article Snippet: D OCR measurement in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ (TargetMol, USA, T2796) restoration.

Techniques: Western Blot, Expressing, Isolation, Software, Sampling, Staining, Immunohistochemistry, Immunofluorescence, Control, Two Tailed Test

A Gene set enrichment analysis derived from the single-cell transcriptome profiling of the wound margin tissue showing the differential biological processes in the pericyte clusters between MAT2A LOF group and control group. NES, Nominal Enrichment Score. FDR P values were calculated based on the one-tailed test on the appropriate side of the null distribution. B Gene set variation analysis derived from the single-cell transcriptome profiling showing the significant enrichment of senescence-related pathway terms in the pericyte clusters. C Box plot showing the recommendation indices of six SIDs for the pericyte cluster ( n = 2211 cells), with SID3 presenting the highest values. D Box plot showing the SID3 scores of pericyte clusters between the MAT2A LOF ( n = 1025 cells) and control groups ( n = 1186 cells). E UMAP plots showing the distribution of SID3 scores of pericyte clusters in the indicated groups. F Immunostaining and statistical analysis of P21 (Red) and NG2 (Green) in cutaneous wound tissues between the control group and the MAT2A LOF group. Scale bar, 20 μm. G Effect of Mat2a knockdown on pericyte senescence, as determined by SAHF formation (H3K9me3 staining) and SA-β-gal staining. Pericytes were isolated from the mouse skins. H Western blot analysis determining the expression levels of P21 and Lamin B1 of pericytes in the indicated groups. I , J OCR measurement and maximal respiration analysis of pericytes with or without Mat2a knockdown. K Bar plot showing the cellular ATP levels of pericytes with or without Mat2a knockdown. L Bar plots showing MAT2A mRNA levels in cells from humans and mice. For the box plots in ( C ), and ( D ), the centerlines indicated the medians. The box limits indicated the first and third quartiles. The whiskers indicated the maxima and minima. Data in the bar plots were shown as mean ± SD. n = 3 biologically independent samples ( F , G , I , J , K ). Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons test ( G ) and two-tailed unpaired t test ( D , F , J , K ). Source data are provided as a Source Data file.

Journal: Nature Communications

Article Title: A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models

doi: 10.1038/s41467-025-65659-2

Figure Lengend Snippet: A Gene set enrichment analysis derived from the single-cell transcriptome profiling of the wound margin tissue showing the differential biological processes in the pericyte clusters between MAT2A LOF group and control group. NES, Nominal Enrichment Score. FDR P values were calculated based on the one-tailed test on the appropriate side of the null distribution. B Gene set variation analysis derived from the single-cell transcriptome profiling showing the significant enrichment of senescence-related pathway terms in the pericyte clusters. C Box plot showing the recommendation indices of six SIDs for the pericyte cluster ( n = 2211 cells), with SID3 presenting the highest values. D Box plot showing the SID3 scores of pericyte clusters between the MAT2A LOF ( n = 1025 cells) and control groups ( n = 1186 cells). E UMAP plots showing the distribution of SID3 scores of pericyte clusters in the indicated groups. F Immunostaining and statistical analysis of P21 (Red) and NG2 (Green) in cutaneous wound tissues between the control group and the MAT2A LOF group. Scale bar, 20 μm. G Effect of Mat2a knockdown on pericyte senescence, as determined by SAHF formation (H3K9me3 staining) and SA-β-gal staining. Pericytes were isolated from the mouse skins. H Western blot analysis determining the expression levels of P21 and Lamin B1 of pericytes in the indicated groups. I , J OCR measurement and maximal respiration analysis of pericytes with or without Mat2a knockdown. K Bar plot showing the cellular ATP levels of pericytes with or without Mat2a knockdown. L Bar plots showing MAT2A mRNA levels in cells from humans and mice. For the box plots in ( C ), and ( D ), the centerlines indicated the medians. The box limits indicated the first and third quartiles. The whiskers indicated the maxima and minima. Data in the bar plots were shown as mean ± SD. n = 3 biologically independent samples ( F , G , I , J , K ). Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons test ( G ) and two-tailed unpaired t test ( D , F , J , K ). Source data are provided as a Source Data file.

Article Snippet: D OCR measurement in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ (TargetMol, USA, T2796) restoration.

Techniques: Derivative Assay, Single Cell, Control, One-tailed Test, Immunostaining, Knockdown, Staining, Isolation, Western Blot, Expressing, Two Tailed Test

$A Bubble map showing the interactions of selected ligand-receptor pairs between pericytes and macrophage subsets. The communication strengths of interacting molecule 1 in cluster 1 and interacting molecule 2 in cluster 2 were indicated by color gradients (blue, low level; red, high level). The P values were calculated with the CellChat one-sided permutation test and indicated by the circle size. B Top panel: The coculture workflow of pericytes with or without Mat2a knockdown and macrophages (bone marrow-derived macrophages). Bottom panel: RT-qPCR analysis of inflammatory signature genes in macrophages. In the contact coculture system, the macrophages were collected through magnetic bead cell sorting (MACS). The workflow was created with BioRender.com. C Heatmap representing the change direction of senescence associated secretion phenotype in pericytes within the wound margin of the indicated groups. D In vitro RT-qPCR verifying the expression of a subset of typical SASP factors in pericytes with or without Mat2a knockdown. E Bar plots showing the Rcm values across a wide range of rank cutoffs (10%-100%) for pericytes within the wound margin of the MAT2A LOF group and the control group. The labels A1-A3 and B1-B3 represent the sample numbers within the groups. F Violin plots depicting the estimated strength (left) and fraction (right) of macrophage-derived mitochondria in pericytes predicted by MERCI between the MAT2A LOF group (n = 154 cells) and control group (n = 184 cells). G In vitro coculture of GFP+ pericytes and mitoDsRed+ macrophages immunostained with β-actin (white) to visualize the membrane boundaries of the two cell types, emphasized with high magnification. Arrows indicate transferred mitoDsRed+ mitochondria in pericytes. Scale bar, 10 μm.For the violin-box plots in ( F ), the centerlines indicated the medians. The box limits indicated the first and third quartiles. The whiskers indicated the maxima and minima. Data in the bar plots were shown as mean ± SD. n = 3 biologically independent samples ( B , D , G ). Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons test ( D ) and two-tailed unpaired t test ( B , F , G ). Source data are provided as a Source Data file.$

Journal: Nature Communications

Article Title: A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models

doi: 10.1038/s41467-025-65659-2

Figure Lengend Snippet: A Bubble map showing the interactions of selected ligand-receptor pairs between pericytes and macrophage subsets. The communication strengths of interacting molecule 1 in cluster 1 and interacting molecule 2 in cluster 2 were indicated by color gradients (blue, low level; red, high level). The P values were calculated with the CellChat one-sided permutation test and indicated by the circle size. B Top panel: The coculture workflow of pericytes with or without Mat2a knockdown and macrophages (bone marrow-derived macrophages). Bottom panel: RT-qPCR analysis of inflammatory signature genes in macrophages. In the contact coculture system, the macrophages were collected through magnetic bead cell sorting (MACS). The workflow was created with BioRender.com. C Heatmap representing the change direction of senescence associated secretion phenotype in pericytes within the wound margin of the indicated groups. D In vitro RT-qPCR verifying the expression of a subset of typical SASP factors in pericytes with or without Mat2a knockdown. E Bar plots showing the Rcm values across a wide range of rank cutoffs (10%-100%) for pericytes within the wound margin of the MAT2A LOF group and the control group. The labels A1-A3 and B1-B3 represent the sample numbers within the groups. F Violin plots depicting the estimated strength (left) and fraction (right) of macrophage-derived mitochondria in pericytes predicted by MERCI between the MAT2A LOF group (n = 154 cells) and control group (n = 184 cells). G In vitro coculture of GFP+ pericytes and mitoDsRed+ macrophages immunostained with β-actin (white) to visualize the membrane boundaries of the two cell types, emphasized with high magnification. Arrows indicate transferred mitoDsRed+ mitochondria in pericytes. Scale bar, 10 μm.For the violin-box plots in ( F ), the centerlines indicated the medians. The box limits indicated the first and third quartiles. The whiskers indicated the maxima and minima. Data in the bar plots were shown as mean ± SD. n = 3 biologically independent samples ( B , D , G ). Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons test ( D ) and two-tailed unpaired t test ( B , F , G ). Source data are provided as a Source Data file.

Article Snippet: D OCR measurement in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ (TargetMol, USA, T2796) restoration.

Techniques: Knockdown, Derivative Assay, Quantitative RT-PCR, FACS, In Vitro, Expressing, Control, Membrane, Two Tailed Test

A Effect of endogenous Mat2a knockdown followed by restoration of Mat2a WT, MUT1 or SAM (500 μM) on pericyte senescence, as determined by SAHF formation (H3K9me3 staining) and SA-β-gal staining ( n = 3). B Western blot assessment of the expression levels of P21 and Lamin B1 in the indicated pericytes. C – E OCR measurement, maximal respiration analysis and cellular ATP assessment of pericytes following endogenous Mat2a knockdown with Mat2a WT, MUT1 or SAM (500 μM) restoration ( n = 3). F Scheme displaying the procedure used for identifying the specific targets of MAT2A through proteomic and IP-MS analysis. The workflow was created with BioRender.com. G Heatmap showing the change direction of differential proteins in pericytes with or without Mat2a knockdown. H Display showed the differentially regulated proteins, categorized per known or predicted function(s), literature and sequence similarity. Circle size was proportional to the number of differentially expressed proteins. I Intersection of the results from the proteomics and IP-MS analyses. J Scheme displaying the HMGCS1-mediated MVA pathway. K IP and WB analyses showing the interaction of MAT2A and HMGCS1 in 293T cells with indicated transfections. L In vitro binding analysis of MAT2A and HMGCS1 with GST pull-down assays. M Design of MAT2A and HMGCS1 truncations. N IP and WB analysis representing the interactions between Flag-tagged truncated MAT2A and His-tagged PRMT1 proteins in 293T cells. O IP and WB analysis representing the interactions between His-tagged truncated HMGCS1 and Flag-tagged MAT2A proteins in 293T cells. P Molecular docking showing the interaction between MAT2A truncation (slate) and HMGCS1 truncation (cyan). Q Docked positions of MAT2A and HMGCS1 and design of the mutations of binding sites between MAT2A and HMGCS1. R IP and WB analysis of the interactions between FLAG-tagged MAT2A mutation (MUT2) and His-tagged HMGCS1 mutation in 293T cells. Data were shown as mean ± SD. n = 3 biologically independent samples ( A , C , D , E ). Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons test ( A , D , E ). n.s. no significance. Source data are provided as a Source Data file.

Journal: Nature Communications

Article Title: A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models

doi: 10.1038/s41467-025-65659-2

Figure Lengend Snippet: A Effect of endogenous Mat2a knockdown followed by restoration of Mat2a WT, MUT1 or SAM (500 μM) on pericyte senescence, as determined by SAHF formation (H3K9me3 staining) and SA-β-gal staining ( n = 3). B Western blot assessment of the expression levels of P21 and Lamin B1 in the indicated pericytes. C – E OCR measurement, maximal respiration analysis and cellular ATP assessment of pericytes following endogenous Mat2a knockdown with Mat2a WT, MUT1 or SAM (500 μM) restoration ( n = 3). F Scheme displaying the procedure used for identifying the specific targets of MAT2A through proteomic and IP-MS analysis. The workflow was created with BioRender.com. G Heatmap showing the change direction of differential proteins in pericytes with or without Mat2a knockdown. H Display showed the differentially regulated proteins, categorized per known or predicted function(s), literature and sequence similarity. Circle size was proportional to the number of differentially expressed proteins. I Intersection of the results from the proteomics and IP-MS analyses. J Scheme displaying the HMGCS1-mediated MVA pathway. K IP and WB analyses showing the interaction of MAT2A and HMGCS1 in 293T cells with indicated transfections. L In vitro binding analysis of MAT2A and HMGCS1 with GST pull-down assays. M Design of MAT2A and HMGCS1 truncations. N IP and WB analysis representing the interactions between Flag-tagged truncated MAT2A and His-tagged PRMT1 proteins in 293T cells. O IP and WB analysis representing the interactions between His-tagged truncated HMGCS1 and Flag-tagged MAT2A proteins in 293T cells. P Molecular docking showing the interaction between MAT2A truncation (slate) and HMGCS1 truncation (cyan). Q Docked positions of MAT2A and HMGCS1 and design of the mutations of binding sites between MAT2A and HMGCS1. R IP and WB analysis of the interactions between FLAG-tagged MAT2A mutation (MUT2) and His-tagged HMGCS1 mutation in 293T cells. Data were shown as mean ± SD. n = 3 biologically independent samples ( A , C , D , E ). Statistical significance was determined using one-way ANOVA with Tukey’s multiple comparisons test ( A , D , E ). n.s. no significance. Source data are provided as a Source Data file.

Article Snippet: D OCR measurement in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ (TargetMol, USA, T2796) restoration.

Techniques: Knockdown, Staining, Western Blot, Expressing, Protein-Protein interactions, Sequencing, Transfection, In Vitro, Binding Assay, Mutagenesis

A HMGCS1 expression levels in pericytes with Mat2a knockdown followed by transfection of Mat2a WT or MUT2. B HMGCS1 expression levels in pericytes treated with cycloheximide (CHX, 100 μg/ml) for the indicated times (top) and relative HMGCS1 protein levels (bottom). C HMGCS1 expression levels in Mat2a -knockdown pericytes treated with or without 10 μM MG132 for 8 h. D Ubiquitination of HMGCS1 in pericytes with the indicated transfections and treatment with 10 μM MG132 for 8 h. E Identification of ubiquitination related modification factors from IP/MS data. HMGCS1 expression levels in pericytes following Otub1 knockdown with or without WT restoration. The workflow was created with BioRender.com. F Ubiquitination of HMGCS1 in 293T cells with transfection of OTUB1 or the indicated mutant and treatment with 10 μM MG132 for 8 h. G Co-localization analysis of MAT2A, OTUB1 and HMGCS1 by immunofluorescence staining in pericytes. H Binding analysis of HMGCS1 and OTUB1 following MAT2A transfection or not in 293T cells treated with 10 μM MG132 for 8 h. I Ubiquitination of HMGCS1 in 293T cells with the indicated transfection of OTUB1 and MAT2A and treatment with 10 μM MG132 for 8 h. J Binding analysis of HMGCS1 and OTUB1 following MAT2A knockdown or not in 293T cells treated with 10 μM MG132 for 8 h. K Ubiquitination of HMGCS1 in 293T cells with the indicated transfection of OTUB1 and knockdown of MAT2A and treatment with 10 μM MG132 for 8 h. L Co-localization analysis of OTUB1 and HMGCS1 following Mat2a knockdown by immunofluorescence staining in pericytes. Data were shown as mean ± SD. n = 3 biologically independent samples ( B ). Statistical significance was determined using two-way ANOVA with Tukey’s multiple comparisons test ( B ). n.s. no significance. Source data are provided as a Source Data file.

Journal: Nature Communications

Article Title: A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models

doi: 10.1038/s41467-025-65659-2

Figure Lengend Snippet: A HMGCS1 expression levels in pericytes with Mat2a knockdown followed by transfection of Mat2a WT or MUT2. B HMGCS1 expression levels in pericytes treated with cycloheximide (CHX, 100 μg/ml) for the indicated times (top) and relative HMGCS1 protein levels (bottom). C HMGCS1 expression levels in Mat2a -knockdown pericytes treated with or without 10 μM MG132 for 8 h. D Ubiquitination of HMGCS1 in pericytes with the indicated transfections and treatment with 10 μM MG132 for 8 h. E Identification of ubiquitination related modification factors from IP/MS data. HMGCS1 expression levels in pericytes following Otub1 knockdown with or without WT restoration. The workflow was created with BioRender.com. F Ubiquitination of HMGCS1 in 293T cells with transfection of OTUB1 or the indicated mutant and treatment with 10 μM MG132 for 8 h. G Co-localization analysis of MAT2A, OTUB1 and HMGCS1 by immunofluorescence staining in pericytes. H Binding analysis of HMGCS1 and OTUB1 following MAT2A transfection or not in 293T cells treated with 10 μM MG132 for 8 h. I Ubiquitination of HMGCS1 in 293T cells with the indicated transfection of OTUB1 and MAT2A and treatment with 10 μM MG132 for 8 h. J Binding analysis of HMGCS1 and OTUB1 following MAT2A knockdown or not in 293T cells treated with 10 μM MG132 for 8 h. K Ubiquitination of HMGCS1 in 293T cells with the indicated transfection of OTUB1 and knockdown of MAT2A and treatment with 10 μM MG132 for 8 h. L Co-localization analysis of OTUB1 and HMGCS1 following Mat2a knockdown by immunofluorescence staining in pericytes. Data were shown as mean ± SD. n = 3 biologically independent samples ( B ). Statistical significance was determined using two-way ANOVA with Tukey’s multiple comparisons test ( B ). n.s. no significance. Source data are provided as a Source Data file.

Article Snippet: D OCR measurement in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ (TargetMol, USA, T2796) restoration.

Techniques: Expressing, Knockdown, Transfection, Ubiquitin Proteomics, Modification, Protein-Protein interactions, Mutagenesis, Immunofluorescence, Staining, Binding Assay

A Cellular CoQ levels in pericytes with Mat2a knockdown. B MAT2A and HMGCS1 expression levels in pericytes with the indicated transfections. C Cellular CoQ levels in pericytes with Mat2a knockdown followed by transfection of Mat2a MUT2, Hmgcs1 , or not. D OCR measurement in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ (TargetMol, USA, T2796) restoration. E , F ATP assessment and cell viability in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ restoration. G SA-β-gal staining in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ restoration. H Expression levels of P21 and Lamin B1 in pericytes subjected to the indicated treatments. I RT-qPCR analysis showing the expression levels of typical SASP components in pericytes subjected to the indicated treatments. J , K MitoDsRed+ macrophages were co-cultured with GFP+ pericytes following the indicated treatment. GFP+ MitoDsRed+ pericytes were quantified via flow cytometry ( J ), as summarized in ( K ).Data were shown as mean ± SD. n = 3 biologically independent samples ( A , C – G , I , K ). Statistical significance was determined using two-tailed unpaired t test ( A ), one-way ANOVA with Tukey’s multiple comparisons test ( C – E , G , I , K ) and two-way ANOVA with Tukey’s multiple comparisons test ( F ). n.s. no significance. Source data are provided as a Source Data file.

Journal: Nature Communications

Article Title: A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models

doi: 10.1038/s41467-025-65659-2

Figure Lengend Snippet: A Cellular CoQ levels in pericytes with Mat2a knockdown. B MAT2A and HMGCS1 expression levels in pericytes with the indicated transfections. C Cellular CoQ levels in pericytes with Mat2a knockdown followed by transfection of Mat2a MUT2, Hmgcs1 , or not. D OCR measurement in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ (TargetMol, USA, T2796) restoration. E , F ATP assessment and cell viability in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ restoration. G SA-β-gal staining in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ restoration. H Expression levels of P21 and Lamin B1 in pericytes subjected to the indicated treatments. I RT-qPCR analysis showing the expression levels of typical SASP components in pericytes subjected to the indicated treatments. J , K MitoDsRed+ macrophages were co-cultured with GFP+ pericytes following the indicated treatment. GFP+ MitoDsRed+ pericytes were quantified via flow cytometry ( J ), as summarized in ( K ).Data were shown as mean ± SD. n = 3 biologically independent samples ( A , C – G , I , K ). Statistical significance was determined using two-tailed unpaired t test ( A ), one-way ANOVA with Tukey’s multiple comparisons test ( C – E , G , I , K ) and two-way ANOVA with Tukey’s multiple comparisons test ( F ). n.s. no significance. Source data are provided as a Source Data file.

Article Snippet: D OCR measurement in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ (TargetMol, USA, T2796) restoration.

Techniques: Knockdown, Expressing, Transfection, Staining, Quantitative RT-PCR, Cell Culture, Flow Cytometry, Two Tailed Test

Harmonious cellular communication and cooperation, as well as efficient transformation of cell phenotypes, are indispensable for wound regeneration. MAT2A downregulation mediated pericyte senescence in a moonlighting manner, which induced the infiltration of inflammatory macrophages in diabetic wounds. This discovery provides an saRNA-based strategy targeting senescent pericytes for wound healing. The diagram was created with BioRender.com.

Journal: Nature Communications

Article Title: A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models

doi: 10.1038/s41467-025-65659-2

Figure Lengend Snippet: Harmonious cellular communication and cooperation, as well as efficient transformation of cell phenotypes, are indispensable for wound regeneration. MAT2A downregulation mediated pericyte senescence in a moonlighting manner, which induced the infiltration of inflammatory macrophages in diabetic wounds. This discovery provides an saRNA-based strategy targeting senescent pericytes for wound healing. The diagram was created with BioRender.com.

Article Snippet: D OCR measurement in pericytes with Mat2a knockdown followed by transfection of Hmgcs1 , or CoQ (TargetMol, USA, T2796) restoration.

Techniques: Transformation Assay

Journal: Cell Reports Medicine

Article Title: Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma

doi: 10.1016/j.xcrm.2025.101977

Figure Lengend Snippet: Reversing CD8A + T cell deficiency by methionine metabolism intervention enhancing immunotherapy response in MTAP-deleted osteosarcoma (A) Flowchart depicting methionine restriction diet combined with immune checkpoint therapy. (B and C) In vivo orthotopic tibia models of DuNN shMtap in C3H mice, depicting tumor growth curves (mean ± SD) and tumor weights at experimental endpoints, treated by methionine restriction diet combined with immune checkpoint therapy. ND n = 8; ICT n = 8; MR n = 8; Combined n = 8. Statistical analyses were performed using two-tailed Student’s t tests. (D) Metabolomics of the intestines in DuNN shMtap tumor-bearing C3H mice revealed downregulation of methionine-related metabolites following dietary methionine restriction. (E) Pathological characteristics and immunohistochemistry (CD8A) of tumor tissues from DuNN shMtap in C3H mice, treated by methionine restriction diet combined with immune checkpoint therapy. Arrows indicate T cells. Scale bar, 100 μm (F) Flowchart depicting MAT2A inhibition combined with immune checkpoint therapy. (G and H) In vivo orthotopic tibia models of DuNN shMtap in C3H mice, depicting tumor growth curves (mean ± SD) and survival curve at experimental endpoints, treated by MAT2A inhibition combined with immune checkpoint therapy. ND n = 6; ICT n = 6; MR n = 6; Combined n = 6. Statistical analyses were performed using two-tailed Student’s t tests. (I) Pathological characteristics and immunohistochemistry (CD8A, CD4, and FOXP3) of tumor tissues from DuNN shMtap in C3H mice, treated by MAT2A inhibition combined with immune checkpoint therapy. Arrows indicate T cells. Scale bar, 100 μm.

Article Snippet: MAT2A protein , Pharmaron Inc. , This study.

Techniques: In Vivo, Two Tailed Test, Immunohistochemistry, Inhibition

Journal: Cell Reports Medicine

Article Title: Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma

doi: 10.1016/j.xcrm.2025.101977

Figure Lengend Snippet: MAT2A inhibition triggering IKZF1-mediated PD-L1 expression in MTAP-deleted osteosarcoma (A, B, and C) Integrated analysis of transcription factors associated with PD-L1 expression in SGH-OS and TARGET-OS and genes upregulated by treating with MAT2A inhibitor rather than immune checkpoint therapy. Spearman correlation tests were performed, and data with p values < 0.05 were considered statistically significant. (D and E) Protein expression of MAT2A and PD-L1 in MTAP-deleted OS cells (143B) treated with MAT2A inhibitor PF-9366, and protein expression of IKZF1, MAT2A, and PD-L1 in 143B cells co-treated with siIKZF1, assessed by western blotting. (F) IKZF1 RNA expression in wild-type (WT) ( n = 36) and MTAP-deleted (DEL) ( n = 14) cases in SGH-OS cohort. Statistical analyses were performed using two-tailed Student’s t tests. (G) Transcriptomic pathway analysis of cells by treating with PF-9366, using GSEA analysis ( p value < 0.05) on Hallmark gene sets. ES refers to enrichment score, and NES refers to normalized enrichment score. (H and I) Survival curve of TARGET-OS and TCGA-SARC related with IKZF1 expression. Statistical significance was calculated using the log rank test. (J) Summary schematic illustrating the mechanism of methionine intervention enhancing immune checkpoint therapy in MTAP-deleted osteosarcoma (MTAP-del OS).

Article Snippet: MAT2A protein , Pharmaron Inc. , This study.

Techniques: Inhibition, Expressing, Western Blot, RNA Expression, Two Tailed Test

Journal: Cell Reports Medicine

Article Title: Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma

doi: 10.1016/j.xcrm.2025.101977

Figure Lengend Snippet:

Article Snippet: MAT2A protein , Pharmaron Inc. , This study.

Techniques: Control, Recombinant, Saline, Red Blood Cell Lysis, Lysis, Staining, Screening Assay, Transfection, Plasmid Preparation, In Vitro, CCK-8 Assay, Cell Isolation, Gene Expression, Sequencing, Methylation, In Vivo, Software, Microscopy, Refractive Index, Mass Spectrometry

SCR‐7952 inhibition on MAT2A. (A) Inhibition of MAT2A enzyme in biochemical assay, (B) and (C) kinetic analysis of SCR‐7952 on MAT2A, and (D) binding response of SCR‐7952 to MAT2A protein by SPR.

Journal: MedComm

Article Title: SCR‐7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the S ‐adenosylmethionine‐competitive or the methylthioadenosine‐cooperative protein arginine methyltransferase 5 inhibitors in methylthioadenosine phosphorylase‐deleted tumors

doi: 10.1002/mco2.705

Figure Lengend Snippet: SCR‐7952 inhibition on MAT2A. (A) Inhibition of MAT2A enzyme in biochemical assay, (B) and (C) kinetic analysis of SCR‐7952 on MAT2A, and (D) binding response of SCR‐7952 to MAT2A protein by SPR.

Article Snippet: MAT2A protein (Cat. 210405‐HWR‐20210429) was bought from Pharmaron.

Techniques: Inhibition, Binding Assay

Crystal structure of MAT2A bound to SCR‐7952. (A) Cryo‐EM structure for MAT2A·SAM·SCR‐7952 (PDB ID 8XJ2), (B) the surface of the SCR‐7952 binding pocket (green for one monomer and pink for the second monomer), and (C) schematic diagram of two‐dimensional interaction for SCR‐7952 (Drawing in Molecular Operating Environment).

Journal: MedComm

doi: 10.1002/mco2.705

Figure Lengend Snippet: Crystal structure of MAT2A bound to SCR‐7952. (A) Cryo‐EM structure for MAT2A·SAM·SCR‐7952 (PDB ID 8XJ2), (B) the surface of the SCR‐7952 binding pocket (green for one monomer and pink for the second monomer), and (C) schematic diagram of two‐dimensional interaction for SCR‐7952 (Drawing in Molecular Operating Environment).

Article Snippet: MAT2A protein (Cat. 210405‐HWR‐20210429) was bought from Pharmaron.

Techniques: Cryo-EM Sample Prep, Binding Assay

Regulation of PRMT5 downstream and splicing events. (A) Immunoblot analysis of SDMA and MAT2A after SCR‐7952 treatment for 96 h, and (B) RT‐PCR of expressions of FANCA and the DI‐containing transcripts after SCR‐7952 or AG‐270 treatment for 72 h in HCT116 WT or MTAP ‐deleted cells. The protein grayscale analysis was performed by ImageJ 1.54d, normalized to vinculin.

Journal: MedComm

doi: 10.1002/mco2.705

Figure Lengend Snippet: Regulation of PRMT5 downstream and splicing events. (A) Immunoblot analysis of SDMA and MAT2A after SCR‐7952 treatment for 96 h, and (B) RT‐PCR of expressions of FANCA and the DI‐containing transcripts after SCR‐7952 or AG‐270 treatment for 72 h in HCT116 WT or MTAP ‐deleted cells. The protein grayscale analysis was performed by ImageJ 1.54d, normalized to vinculin.

Article Snippet: MAT2A protein (Cat. 210405‐HWR‐20210429) was bought from Pharmaron.

Techniques: Western Blot, Reverse Transcription Polymerase Chain Reaction

Synergistic activity of SCR‐7952 in combination with the PRMT5 inhibitor. (A) Drug dose–response curves for proliferation inhibition and (B) Bliss plots showing synergistic effects of the combination of SCR‐7952 and JNJ‐64619178 on HCT116 MTAP −/− cells for 8 days. (C) Immunoblot analysis of SDMA and MAT2A after combination treatment for 96 h, and (D) RT‐PCR of expressions of FANCA and the DI‐containing transcripts after SCR‐7952 treatment for 72 h. (E) Impact of SCR‐7952 and JNJ‐64619178 alone and in combination on tumor growth, (F) body weights, and (G) tumor SDMA levels on HCT116 MTAP −/− tumor‐bearing mice (mean ± SEM, n = 8).

Journal: MedComm

doi: 10.1002/mco2.705

Figure Lengend Snippet: Synergistic activity of SCR‐7952 in combination with the PRMT5 inhibitor. (A) Drug dose–response curves for proliferation inhibition and (B) Bliss plots showing synergistic effects of the combination of SCR‐7952 and JNJ‐64619178 on HCT116 MTAP −/− cells for 8 days. (C) Immunoblot analysis of SDMA and MAT2A after combination treatment for 96 h, and (D) RT‐PCR of expressions of FANCA and the DI‐containing transcripts after SCR‐7952 treatment for 72 h. (E) Impact of SCR‐7952 and JNJ‐64619178 alone and in combination on tumor growth, (F) body weights, and (G) tumor SDMA levels on HCT116 MTAP −/− tumor‐bearing mice (mean ± SEM, n = 8).

Article Snippet: MAT2A protein (Cat. 210405‐HWR‐20210429) was bought from Pharmaron.

Techniques: Activity Assay, Inhibition, Western Blot, Reverse Transcription Polymerase Chain Reaction

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