EPMA J. 2026 Aug 21;17(3):665-700. doi: 10.1007/s13167-026-00465-4. eCollection 2026 Sep.

ABSTRACT

Chronic atrophic gastritis (CAG) is a critical precancerous stage in the development of gastric cancer (GC). Circadian rhythm disruption perturbs the core clock gene network, including circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT-like 1 (BMAL1), period circadian protein homolog (PER), and cryptochrome (CRY). These alterations contribute to a multi-layered pathological cascade involving DNA damage accumulation, epigenetic remodeling, altered epithelial cell plasticity, cellular senescence, microbiota dysbiosis, tumor microenvironment remodeling, metabolic reprogramming, aberrant angiogenesis, and dysregulated cell death, thereby accelerating CAG to GC progression. However, existing studies have predominantly treated the circadian rhythm as a passive risk factor for disease onset and have yet to elevate it to an actionable interventional target within the full-course management of gastric precancerous lesions. Building on a systematic synthesis of the mechanistic evidence outlined above, this review proposes a predictive, preventive and personalised medicine (PPPM/3PM) three-tier management framework grounded in circadian-based individualised protection. At the predictive level, digital biomarkers (sleep-wake rhythms, light exposure, physical activity, and dietary behavior), multi-omics profiles, and circadian-related molecular signatures are integrated to achieve dynamic risk stratification of CAG populations. At the targeted prevention level, pharmacological agents and natural compounds with circadian-regulating potential are deployed to develop proactive protective strategies tailored to distinct pathological stages and circadian phenotypes. At the personalised treatment level, lifestyle interventions, chronotherapy, nano-carrier-based circadian-synchronised delivery, and dynamic biomarker monitoring are combined to formulate precision intervention regimens informed by individual circadian phenotypes. This framework repositions the circadian rhythm from a latent risk factor to a protectable and therapeutically targetable axis, offering new insights into time-optimised intervention strategies for the inflammation to cancer transition in CAG.

PMID:42682657 | PMC:PMC13530114 | DOI:10.1007/s13167-026-00465-4

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

Cancer Discov. 2026 Apr 15. doi: 10.1158/2159-8290.CD-25-1663. Online ahead of print.

ABSTRACT

Brain metastases (BM) remain a devastating disease with dismal prognosis. How circulating tumor cells (CTCs) penetrate the blood brain barrier (BBB) and reprogram the brain microenvironment remain unclear. Using spatially resolved multi-omic profiling of CTCs and brain metastases, integrated with experimental and clinical analyses, we identified Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) as a CTC-secreted driver of vascular disruption and brain colonization. CBX3 upregulation induced GPNMB expression, which bound endothelial EGFR, triggering CBL-mediated ubiquitination and degradation. Attenuated EGFR signaling suppressed FTO and disrupted endothelial junctions via YTHDF2-dependent TJP1 m6A methylation. Remarkably, GPNMB-induced BBB remodeling promoted immune infiltration via CXCL12-CXCR4 axis, and induced time course-dependent T cell exhaustion within the brain microenvironment. Clinically, elevated CBX3⁺GPNMB⁺ CTCs and plasma CXCL12 were significantly associated with BM progression in lung cancer and melanoma. Therapeutically, dual blockade of GPNMB and PD1 enhanced anti-BM efficacy in mice, unveiling GPNMB as a promising target for precision immunotherapy.

PMID:41973996 | DOI:10.1158/2159-8290.CD-25-1663

J Pharm Biomed Anal. 2026 Mar 29;276:117486. doi: 10.1016/j.jpba.2026.117486. Online ahead of print.

ABSTRACT

Patients with polycystic ovary syndrome (PCOS) are at an elevated risk of depression, yet the underlying mechanisms remain elusive. Emerging evidence implicates the gut-brain axis and systemic lipid homeostasis alterations as potential key contributors. We profiled untargeted plasma lipidomes of PCOS patients with and without comorbid depression (PCOS-DP) and integrated these data with our prior gut microbial and host transcriptomic datasets to construct multi-omics interaction networks. The causal role of the candidate gut microbial was preliminary explored in a germ-free PCOS mouse model using fecal microbiota transplantation, followed by behavioral phenotyping and ELISA-based protein quantification. We identified a distinct plasma lipidomic signature differentiating PCOS-DP from PCOS alone, characterized primarily by the downregulation of 26 lipid species. Most of these altered lipids were triacylglycerols (TAGs) enriched with FA18:1 and FA18:2, whose levels correlated with coagulation dysfunction. Multi-omics network analysis revealed significant interconnections between depression-associated gut microbiota (including Bacteroides eggerthii), specific altered lipids such as TAG (60:12/FA22:6), and host genes involved in inflammation (e.g., IL22, NLRP7), metabolism, and neural processes. Animal validation demonstrated that B. eggerthii colonization in PCOS mice specifically exacerbated anhedonia and hyperlocomotion, alongside modulating plasma IL-22 expression, suggesting its context-dependent neurobehavioral effect role. This study delineates a TAG-downregulated lipid signature with diagnostic potential and reveals a novel "gut microbiota-lipid-host gene" interaction network underpinning PCOS-DP, with B. eggerthii as a key microbial modulator of neurobehavioral phenotypes in the context of PCOS. These findings provide new pathophysiological insights and highlights potential diagnostic biomarkers for PCOS-DP.

PMID:41924769 | DOI:10.1016/j.jpba.2026.117486

Tissue Cell. 2026 Mar 10;101:103409. doi: 10.1016/j.tice.2026.103409. Online ahead of print.

ABSTRACT

Gastric cancer (GC) remains a major global health burden, with high incidence and mortality rates, particularly in East Asia, driven by factors such as Helicobacter pylori infection, dietary risks, and genetic predispositions. Conventional treatments like surgery and chemotherapy are limited by resistance, toxicity, and poor outcomes in advanced stages. The PI3K/Akt/mTOR and MAPK signaling pathways are central to GC pathogenesis, promoting proliferation, survival, metabolic reprogramming, epithelial-mesenchymal transition (EMT), and metastasis through aberrations like PIK3CA mutations, PTEN loss, and KRAS alterations. These pathways exhibit extensive crosstalk, contributing to therapeutic resistance. This review explores the regulatory effects of Traditional Chinese Medicine (TCM) on these pathways in GC, grounded in TCM principles such as Qi deficiency, Damp-Heat, and disharmony of the Spleen and Stomach. Single herbal monomers (e.g., curcumin, berberine, resveratrol) inhibit PI3K/Akt/mTOR by upregulating PTEN and suppressing mTOR, inducing autophagy and apoptosis. Classical herbs like Huangqin and Huanglian modulate Akt and ERK phosphorylation, while compound formulas (e.g., Banxia Xiexin Decoction, Sijunzi Decoction) synergistically target both pathways, reversing EMT and chemoresistance. TCM addresses crosstalk by disrupting feedback loops and reducing inflammation, enhancing efficacy in combination with Western therapies like chemotherapy and immunotherapy. Network pharmacology and multi-omics analyses reveal TCM's multitarget mechanisms, aligning with ZHENG-based personalization. Challenges include research variability, standardization issues, and incomplete mechanistic validation. Future directions emphasize high-quality trials, omics integration, and precision TCM for clinical translation. TCM offers low-toxicity, holistic options for integrative GC management, potentially improving survival and quality of life.

PMID:41825157 | DOI:10.1016/j.tice.2026.103409

Tissue Cell. 2026 Mar 10;101:103409. doi: 10.1016/j.tice.2026.103409. Online ahead of print.

ABSTRACT

Gastric cancer (GC) remains a major global health burden, with high incidence and mortality rates, particularly in East Asia, driven by factors such as Helicobacter pylori infection, dietary risks, and genetic predispositions. Conventional treatments like surgery and chemotherapy are limited by resistance, toxicity, and poor outcomes in advanced stages. The PI3K/Akt/mTOR and MAPK signaling pathways are central to GC pathogenesis, promoting proliferation, survival, metabolic reprogramming, epithelial-mesenchymal transition (EMT), and metastasis through aberrations like PIK3CA mutations, PTEN loss, and KRAS alterations. These pathways exhibit extensive crosstalk, contributing to therapeutic resistance. This review explores the regulatory effects of Traditional Chinese Medicine (TCM) on these pathways in GC, grounded in TCM principles such as Qi deficiency, Damp-Heat, and disharmony of the Spleen and Stomach. Single herbal monomers (e.g., curcumin, berberine, resveratrol) inhibit PI3K/Akt/mTOR by upregulating PTEN and suppressing mTOR, inducing autophagy and apoptosis. Classical herbs like Huangqin and Huanglian modulate Akt and ERK phosphorylation, while compound formulas (e.g., Banxia Xiexin Decoction, Sijunzi Decoction) synergistically target both pathways, reversing EMT and chemoresistance. TCM addresses crosstalk by disrupting feedback loops and reducing inflammation, enhancing efficacy in combination with Western therapies like chemotherapy and immunotherapy. Network pharmacology and multi-omics analyses reveal TCM's multitarget mechanisms, aligning with ZHENG-based personalization. Challenges include research variability, standardization issues, and incomplete mechanistic validation. Future directions emphasize high-quality trials, omics integration, and precision TCM for clinical translation. TCM offers low-toxicity, holistic options for integrative GC management, potentially improving survival and quality of life.

PMID:41825157 | DOI:10.1016/j.tice.2026.103409