Biomedical subjects

Tuo Zhang

Publications and source records attributed to Tuo Zhang.

5 recordsLinked to original sources

PubMed2026

Reprogramming of TLR-Ferroptosis Signaling and Immunometabolic Pathways Overcomes Myeloid Suppression to Improve Checkpoint Blockade in Prostate Cancer.

UNLABELLED: The limited efficacy of immunotherapies in advanced prostate cancer stems from a tumor microenvironment (TME) in which myeloid-driven immune suppression, stromal remodeling, and metabolic barriers converge to limit antitumor immunity. In this study, we characterized the immunometabolic properties of an ultrasmall prostate-specific membrane antigen-targeting silica particle therapy as a first-in-class strategy to reprogram the Toll-like receptor (TLR)-ferroptosis axis in MYC-driven prostate cancer. As single agents, these particles suppressed lipid and steroid biosynthesis, disrupted lipid peroxidation control, and impaired nutrient flux, sensitizing tumors to ferroptosis. Coordinated redox remodeling, stromal reprogramming, and innate immune activation reversed myeloid suppression and promoted CD8+ T-cell infiltration. When combined with CSF-1R inhibition and immune checkpoint blockade, the particles suppressed tumor growth, extended survival beyond 100 days, and achieved up to 50% complete remission in MYC-overexpressing models. These findings position TLR-ferroptosis axis remodeling as a mechanistic blueprint for rational, particle-driven immunotherapies with broad translational potential in prostate cancer and other immunologically refractory malignancies. SIGNIFICANCE: Clinically validated, PSMA-targeted ultrasmall core-shell silica particles reprogram immunometabolic pathways via a TLR-ferroptosis axis, enabling tumor microenvironment remodeling and potentiating checkpoint blockade in prostate cancer, with translational implications for treatment-resistant disease.

Male↗

PubMed2025

Dual genetic loci and flavonoid metabolism orchestrate fruiting body coloration in Flammulina filiformis: a multi-omic roadmap for fungal pigmentation.

BACKGROUND: The fruiting bodies of macrofungi exhibit diverse coloration, traditionally attributed to melanin and carotenoid biosynthesis. This study is the first to reveal that flavonoids, rather than these classical pigments, are the predominant contributors to yellow pigmentation in the Flammulina filiformis. OBJECTIVE: To uncover the genetic basis and key regulatory genes involved in pigment formation in F. filiformis fruiting bodies, and to establish a model framework for studying color genetics in macrofungi. METHODS: Metabolomic profiling was conducted on yellow and white F. filiformis fruiting bodies to identify key pigment components. A segregating population was constructed, followed by integrated multi-omics analyses-including bulk segregant analysis (BSA), genome-wide association study (GWAS), and transcriptomics-to map regulatory loci and candidate genes. Functional roles were validated via genetic transformation and protein structural modeling. RESULTS: Flavonoid accumulation was identified as the biochemical hallmark of pigmented fruiting bodies. Genetic analysis revealed a dual regulatory mechanism: a qualitative locus governing pigmentation presence and a quantitative trait determining color intensity. Combined BSA and GWAS pinpointed a major locus, Ffcrs, within a recombination-suppressed region. Transcriptomic analysis identified two key regulators, Ffakr (a transcriptional activator) and Ffpal (encoding phenylalanine ammonia-lyase). Functional verification via transformation, structural modeling, and metabolite profiling in transgenic lines confirmed their essential roles in flavonoid biosynthesis and pigmentation. CONCLUSION: This study uncovers a flavonoid-based pigmentation mechanism in F. filiformis and elucidates a complex genetic architecture shaped by both qualitative and quantitative loci, providing a new paradigm for understanding pigment formation in macrofungi. The identified regulatory factors establish a molecular foundation for the precise manipulation of economically important pigmentation traits in edible mushroom.

Flavonoids↗

PubMed2025

De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.

Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.

Pyrimidines↗

PubMed2025

ChemPerturb-seq screen identifies a small molecule cocktail enhancing human beta cell survival after subcutaneous transplantation.

Traditional chemical screens have focused on a single assay per screen, making them labor intensive and costly. Here, we combined a chemical screen with single-cell RNA sequencing (scRNA-seq) to perform Chemical Perturb-seq (ChemPerturb-seq), enabling a systematic analysis of the molecular changes of human beta cells upon individual small molecule treatments. Using this platform, we performed an in vivo barcoded screen and discovered a small molecule cocktail, including beta-lipotropin 61-91, insulin growth factor-1, and prostaglandin E2, with which preconditioning human beta cells and primary islets significantly enhanced function and survival when transplanted subcutaneously to female, but not to male, mice. We identified two additional molecules, serotonin and histamine, that promote islet function when transplanted subcutaneously to male mice using ChemPerturb-seq. Such small molecule cocktails could be applied to improve the current FDA-approved islet transplantation procedure. Finally, we developed an artificial intelligence (AI)-powered website, ChemPerturbDB, which provides user-friendly open access analysis of the extensive ChemPerturb-seq dataset.

Humans↗

PubMed2025

Exogenous BMI1 expression aggravates oral squamous cell carcinomas in tongue epithelia.

Oral squamous cell carcinoma (OSCC) is characterized by aggressiveness and a poor prognosis, in part because most patients are diagnosed during the later stages of the disease. B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), part of polycomb repressive complex 1 (PRC1), is a key transcription factor overexpressed in OSCC. Although increased BMI1 has been linked to tumor formation in mouse models of the disease, the molecular mechanisms have not been elucidated. Here we used a transgenic mouse line (KrTB) that selectively overexpresses BMI1 in the tongue basal epithelial stem cells (SCs) to delineate BMI1 actions during oral tumorigenesis. By tumor pathological classification after 4-nitroquinoline 1-oxide (4-NQO)-induced carcinogenesis we detected more severe tumors in mice with ectopic BMI1 expression. Genome-wide transcriptomics indicated that mRNAs associated with human OSCC, including SOX9, HIF1A, MMP9, INHBB, and MYOF, were further increased by ectopic BMI1 expression in murine tongue epithelia. mRNAs encoding multiple metabolic targets, such as SLC2A1 (GLUT1), PKM, LDHA, and HK2, were also increased upon BMI1 overexpression in 4-NQO-treated tongue epithelia. Furthermore, we detected BMI1, SOX9, and GLUT1 proteins in the infiltrating cells of invasion fronts identified by markers of invasive SCCs. Finally, metabolomic data show that BMI1 overexpression in tongue epithelia promotes glycolysis during 4-NQO-induced carcinogenesis. Thus, our data demonstrate that BMI1 causes OSCC cells to alter cell metabolism, as changes in many of these transcripts are linked to increased glycolysis and metabolic reprograming that occurs during carcinogenesis.

Animals↗