Free Radic Biol Med. 2026 Sep 9;256:441-460. doi: 10.1016/j.freeradbiomed.2026.09.006. Online ahead of print.

ABSTRACT

Gestational diabetes mellitus (GDM) is a common pregnancy complication with a rising global prevalence, posing serious short-term and long-term health threats to both mothers and offspring. This review repositions GDM as a systemic disorder in which oxidative stress acts as a proposed mechanistic hub, linking upstream risk factors to downstream pathophysiology. We first examine how "upstream" factors-including genetic susceptibility, pre-conception status, and environmental exposures-converge to promote a state of pathological redox imbalance. We then examine key mechanistic pathways through which oxidative stress is thought to contribute to systemic insulin resistance and pancreatic β-cell failure, highlighting novel pathways involving intercellular communication via tunneling nanotubes and exosomes. Furthermore, we explore the downstream cascade, where oxidative stress may program maternal accelerated biological aging and multi-organ offspring disease trajectories through nuclear epigenetic programming and mitochondrial dysfunction programming, leaving what has been termed a persistent "metabolic memory". Consequently, this review evaluates emerging strategies that target oxidative stress for early prediction and precision intervention. Early prediction models based on direct redox biomarkers and multi-omics signatures hold potential to shift diagnosis from late-gestation oral glucose tolerance test (OGTT) to first-trimester risk stratification. Current supporting evidence draws from human epidemiological associations, ex vivo placental analyses, and experimental models. However, direct causal and interventional validation in pregnant women remains limited. Integrating targeted redox risk stratification and precision interventions into a life-course clinical framework may help interrupt the intergenerational transmission of metabolic disease initiated by GDM.

PMID:42716407 | DOI:10.1016/j.freeradbiomed.2026.09.006

Gut. 2026 Sep 7:gutjnl-2025-337414. doi: 10.1136/gutjnl-2025-337414. Online ahead of print.

ABSTRACT

BACKGROUND: Neutrophils are increasingly recognised as immunosuppressive drivers of hepatocellular carcinoma (HCC), yet their persistence in the oxidative, lipid-rich tumour microenvironment remains poorly understood.

OBJECTIVE: To elucidate the metabolic and molecular programmes that enable tumour-associated neutrophils (TANs) to resist ferroptosis and sustain immunosuppression in HCC.

DESIGN: We employed human HCC samples, multiple murine HCC models, transcriptomic and lipidomic profiling, genetic loss-of-function systems and therapeutic interventions. Ferroptosis sensitivity, lipid metabolic rewiring and immunological consequences of TANs were systematically evaluated across models and validated in patient datasets and biospecimens.

RESULTS: TANs in human HCC and mouse models exhibit pronounced lipid accumulation and oxidative stress compared with peripheral neutrophils. Multi-omic profiling revealed that TANs are enriched for lipid-binding gene programmes and undergo rewiring towards sphingolipid and unsaturated fatty acid metabolism. We identified triggering receptor expressed on myeloid cells 2 (TREM2) as a key lipid-sensing receptor selectively expressed in TANs. Functional deletion of TREM2 reprogrammed the tumour immune microenvironment, restoring CD8⁺ T cell activity and suppressing HCC progression. Mechanistically, tumour-derived sphingosine-1-phosphate (S1P) activates TREM2, triggering nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcription of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby promoting ferroptosis resistance. TREM2 expression is transcriptionally induced by granulocyte-macrophage colony-stimulating factor-signal transducer and activator of transcription 3 (GM-CSF-STAT3) signalling. Genetic deletion of TREM2, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated knockout of sphingosine kinase 1/2 (SPHK1/2) in tumour cells, or pharmacological inhibition of S1P synthesis disrupts this protective lipid-immune circuit, sensitises TANs to ferroptosis and restricts tumour growth. Therapeutically, a peptide-based TREM2 inhibitor reprogrammes TANs, restores CD8⁺ T cell function and enhances anti-programmed cell death protein 1 (PD-1) immunotherapy efficacy. Clinically, TREM2⁺ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in HCC tumours, correlate with SPHK1/2 expression and T cell dysfunction and associate with poor patient prognosis.

CONCLUSION: Our study uncovers the S1P-TREM2-NRF2 axis as a critical metabolic-immune circuit that preserves neutrophil survival and immunosuppressive function in HCC. Targeting this lipid-dependent ferroptosis resistance pathway offers a promising therapeutic strategy to overcome immunotherapy resistance in liver cancer.

PMID:42705697 | DOI:10.1136/gutjnl-2025-337414