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

Chin J Cancer Res. 2026 Aug 30;38(4):480-500. doi: 10.21147/j.issn.1000-9604.2026.04.08.

ABSTRACT

OBJECTIVE: Breast cancer remains a leading cause of global cancer mortality, characterized by profound heterogeneity. While immune checkpoint blockade (ICB) has transformed oncology, its efficacy in breast cancer is often hindered by "immune-cold" microenvironments and immune exclusion. Programmed cell death (PCD) is a critical regulator of tumor immune microenvironment (TIME). However, its role in the breast cancer immune microenvironment remains poorly understood.

METHODS: We integrated multi-omics data from six breast cancer cohorts (N=3,764) to develop a programmed cell death learning signature (PCDsig) using over 100 machine learning combinations. The model was benchmarked against 29 published signatures. Single-cell transcriptomic analysis decoded the immune landscape and cellular crosstalk. The role of adaptor-related protein complex 1 subunit sigma 1 (AP1S1) was validated through a clinical cohort, in vitro functional assays, and in vivo syngeneic mouse models.

RESULTS: PCDsig significantly stratified patient prognosis across all cohorts, consistently outperforming 29 existing models. High PCDsig scores correlated with immune-excluded phenotypes, reduced CD8+ T cell infiltration, and lower immunophenoscores. Single-cell analysis revealed that high-PCDsig tumors utilize vascular endothelial growth factor A (VEGFA) signaling to foster an immunosuppressive microenvironment. AP1S1 was identified as the core driver of immune exclusion. And our clinical cohort supported the immune exclusion effect of AP1S1. AP1S1 knockdown impaired tumor progression in vitro and fundamentally remodeled the tumor immune ecosystem in vivo. Combining AP1S1 inhibition with anti-programmed cell death ligand 1 (anti-PD-L1) therapy exerted profound synergistic effects, driven by massive infiltration and functional activation of cytotoxic Granzyme B (GZMB)+CD8+ T cells.

CONCLUSIONS: Our study establishes the PCDsig we developed is a potential prognostic and predictive biomarker for breast cancer. We provide the first evidence of AP1S1 as a core immunomodulatory oncogene that mediates immune exclusion. Targeting AP1S1 represents a highly promising strategy to sensitize cold breast tumors to ICB, offering a new perspective for precision immunotherapy.

PMID:42712842 | PMC:PMC13551362 | DOI:10.21147/j.issn.1000-9604.2026.04.08

Phytomedicine. 2026 May 15;157:158305. doi: 10.1016/j.phymed.2026.158305. Online ahead of print.

ABSTRACT

BACKGROUND: Severe acute pancreatitis (SAP) lacks targeted therapies, and massive loss of functional pancreatic acinar cells (PAC) drives mortality. Kaempferol (KA) possesses well-established anti-inflammatory and cytoprotective activities and is derived from herbal medicinal plants, but its direct molecular targets and mechanism of action in SAP remain undefined.

PURPOSE: To evaluate the protective effects of KA against SAP and to elucidate its molecular mechanism of specific action, with a focus on identifying the direct cellular target through which KA exerts its cytoprotective effects.

STUDY DESIGN: Gain‑/loss‑of‑function in vitro and PAC‑specific CD47 SAP mouse models, combined with multi‑omics screening and biophysical assays.

METHODS: CD47 manipulation (siRNA/overexpression) was performed in primary PACs and cell lines, combined with WT/CD47^-/-/Mist1‑CD47‑iOE (PAC‑specific) mouse models. Network pharmacology, transcriptomics and proteomics were integrated to screen and validate KA's protective effects. Computational‑experimental approaches (molecular docking/dynamics, CETSA, SPR, co‑IP, pharmacological epistasis) characterized KA's allosteric modulation of CD47 signaling.

RESULTS: CD47 was upregulated in SAP; its knockout reduced PAC death via KEAP1/PGAM5/AIFM1-driven oxeiptosis. KA reduced PAC death across genotypes, afforded no extra benefit in CD47-KO, and was not overridden by CD47‑OE. Mechanistically, KA allosterically binds CD47 ectodomain, stabilizes the CD47‑ UBQLN1 complex, and redirects signaling from Gαi‑mediated death to Gβγ/ ERK/NRF2‑mediated survival. ERK inhibition attenuated KA's protection. KA's action was CD47‑dependent.

CONCLUSION: This study identifies anti-oxeiptosis as a novel pharmacological activity of KA in SAP. This is achieved through allosteric modulation of CD47, redirecting its signaling from death‑promoting to a protective axis via activating Gβγ/ERK/NRF2 to suppress oxeiptosis. These findings reveal the CD47‑oxeiptosis axis as a therapeutic target and position KA as a promising candidate for SAP therapy, adding a new mechanistic dimension to KA's known pharmacological profile.

PMID:42184499 | DOI:10.1016/j.phymed.2026.158305

Dev Cell. 2026 May 19:S1534-5807(26)00159-0. doi: 10.1016/j.devcel.2026.04.012. Online ahead of print.

ABSTRACT

The lack of accurate human models that recapitulate pancreatic ductal adenocarcinoma (PDAC) initiation has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectories of tumor initiation and progression, validated against clinical datasets and tumor histopathology. We demonstrate that CDKN2A loss, which is nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, whereas SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of the pancreatic lineage program during PDAC initiation, alongside AP-1-driven chromatin remodeling. We identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and hypermethylation of essential pancreatic transcription factors. This model captures genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a potential early intervention strategy.

PMID:42161274 | PMC:PMC13196429 | DOI:10.1016/j.devcel.2026.04.012

bioRxiv [Preprint]. 2026 Mar 11:2026.03.09.710586. doi: 10.64898/2026.03.09.710586.

ABSTRACT

The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro , validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of pancreatic lineage program during PDAC initiation, alongside oncogenic AP-1-driven chromatin remodeling. Notably, we identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and the hypermethylation and silencing of essential pancreatic transcription factors. This model captures the genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a promising early intervention strategy for high-risk individuals.

PMID:41959451 | PMC:PMC13060829 | DOI:10.64898/2026.03.09.710586

Cell Rep Med. 2026 Mar 30:102708. doi: 10.1016/j.xcrm.2026.102708. Online ahead of print.

ABSTRACT

Intratumor heterogeneity (ITH) undermines transcriptome-based stratification in intrahepatic cholangiocarcinoma (iCCA). Here, we integrate multi-omics data from multi-region, single-region, and single-cell RNA sequencing cohorts to systematically characterize gene expression ITH. We uncover that immune and stromal heterogeneity are primary drivers of ITH, leading to misclassification of a median 27.8% of tumors by existing subtyping systems. To overcome this, we identify a low-intratumor-heterogeneity/high-intertumor-variability (LIHV) gene set and develop an ITH-insensitive classification system defining five subgroups: inflammatory (SI), metabolic (SII), atypical (SIII-1), immune-silent (SIII-2), and neurodegenerative (SIII-3). These subgroups exhibit distinct clinical outcomes, molecular features, immune landscapes, and therapeutic vulnerabilities. GPRC5A and VTCN1 serve as robust immunohistochemical biomarkers for SI and SIII tumors, while serum CEA and CA19-9 identify inflammatory iCCA. Therapeutically, HSP90 inhibition synergizes with anti-PD1 in inflammatory iCCA, whereas combined anti-PD1 and anti-TIM3 suppresses neurodegenerative iCCA. Collectively, our study provides a robust molecular framework and actionable therapeutic strategies for iCCA.

PMID:41916296 | DOI:10.1016/j.xcrm.2026.102708