Signal Transduct Target Ther. 2026 Sep 4;11(1):363. doi: 10.1038/s41392-026-02936-6.

ABSTRACT

Metabolic reprogramming forms the foundation of immune effector functions and the regulation of inflammation. As a pivotal node connecting the tricarboxylic acid cycle to immune signaling, the IRG1/ACOD1 and itaconate axes play a central role in coordinating inflammatory tone and redox balance. Itaconate, generated through the decarboxylation of cis aconitate, acts as an immunometabolic brake that engages multiple regulatory pathways to sustain the dynamic equilibrium between inflammation and tissue homeostasis. Across a broad spectrum of pathological conditions, including infectious diseases, metabolic disorders, ischemia‒reperfusion injury, neurodegenerative diseases, autoimmune disorders, and cancers, itaconate and its derivatives generally exert anti-inflammatory and cytoprotective effects. However, within specific microenvironments, these molecules may also be exploited by pathogens to evade immune clearance or promote immunosuppressive and protumorigenic responses. Future studies should further elucidate tissue- and lineage-specific functions, define bidirectional regulatory mechanisms, and optimize the pharmacokinetic properties of itaconate derivatives. With the advancement of multiomics integration, systems immunology, rational drug design, and engineered itaconate delivery technologies, the IRG1/ACOD1-itaconate axis and derivative-based therapeutic strategies are poised to emerge as key metabolic checkpoints and therapeutic targets in inflammatory-, metabolic-, immune-, and cancer-related diseases.

PMID:42693110 | PMC:PMC13542262 | DOI:10.1038/s41392-026-02936-6

Clin Transl Med. 2026 Sep;16(9):e70784. doi: 10.1002/ctm2.70784.

ABSTRACT

BACKGROUND: As a pivotal metabolic enzyme, cysteine dioxygenase type 1 (CDO1) exerts tumour-suppressive effects across diverse tumour types, and its expression is strongly correlated with clinical prognosis. However, the molecular mechanisms underlying CDO1-mediated tumour suppression in gastric cancer (GC), its relationship with the tumour-associated immune microenvironment, and pharmacological strategies to restore its expression remain poorly understood.

METHODS: CDO1 expression and prognosis were evaluated by multi-omics and tissue microarray analyses. Tumour microenvironment and immune infiltration were analyzed using ESTIMATE and ssGSEA. Downstream pathways and interacting proteins were identified by transcriptomics, co-immunoprecipitation, and GST pull-down. CDO1 function was assessed by proliferation, apoptosis, and migration assays in gain- and loss-of-function models. In vivo tumorigenesis and CDO1-dependent decitabine efficacy were evaluated by subcutaneous xenografts. Patient-derived organoids were used to assess decitabine sensitivity and 5-FU synergy.

RESULTS: Compared with normal controls, CDO1 expression was notably decreased in GC tissues, and its low expression was strongly linked to unfavourable prognosis, supporting its utility as a biomarker for prognosis. Elevated CDO1 levels correlated with an immune-active tumour microenvironment and reduced metastatic signatures. Mechanistically, CDO1 directly bound to PI3K p85α, disrupting p85α-p110α dimerization, thereby attenuating PI3K/AKT phosphorylation and downregulating THBS1 expression. CDO1 overexpression led to reduced proliferation, invasiveness, and EMT, accompanied by increased apoptosis. These effects were reversed by PI3K activation or THBS1 co-overexpression. Decitabine was identified as an agent that epigenetically restores CDO1 expression. Critically, CDO1 knockdown significantly attenuated the anti-tumour efficacy of decitabine in vivo, confirming that decitabine acts primarily through CDO1 reactivation. Decitabine synergized with 5-FU in both organoids and xenografts.

CONCLUSIONS: Our data identify CDO1 as both a biomarker for prognosis and a tumour suppressor in gastric cancer. They reveal a CDO1-PI3K/AKT-THBS1 signalling axis and support the epigenetic reactivation of CDO1 by decitabine as a translatable therapeutic strategy.

KEY POINTS: CDO1 is frequently downregulated in gastric cancer and serves as an independent favourable prognostic biomarker. CDO1 directly binds PI3K p85α, disrupting p85α-p110α dimerization to suppress the PI3K/AKT-THBS1 signalling axis. Decitabine epigenetically restores CDO1 expression, and its anti-tumour activity is critically CDO1-dependent in vivo. Combining decitabine with 5-FU synergistically overcomes gastric cancer growth in patient-derived organoids and subcutaneous xenograft models.

PMID:42670236 | PMC:PMC13527532 | DOI:10.1002/ctm2.70784