Guangyong Zhang

Gastric cancer (GC) represents a substantial global health challenge and is among the most prevalent and deadly malignancies worldwide. Emerging evidence suggests that protein lactylation plays a pivotal role in the progression of various cancers. However, the specific levels and regulatory mechanisms of protein lactylation in GC remain poorly understood. In this study, we detected elevated pan‐lactylation modification levels in GC tissues. Notably, lactylation at the K406 site of hydroxyacyl‐CoA dehydrogenase (HADHA) was significantly upregulated in GC tissues. This site‐specific lactylation modification enhanced GC progression. Disrupting lactylation at the HADHA ^K406 site markedly reduced its enzymatic activity, thereby mitigating GC progression by impairing fatty acid β‐oxidation and glycolysis. Furthermore, inhibiting HADHA ^K406 lactylation (HADHA K406la) suppressed the HMG‐CoA reductase (HMGCR)‐mediated cholesterol synthesis pathway, which, in turn, improved the immunosuppressive tumor microenvironment in GC. Finally, combining an HMGCR inhibitor with a lactate dehydrogenase A (LDHA) inhibitor effectively enhanced the immune response against GC and inhibited tumor progression. In conclusion, this study demonstrated that HADHA K406la regulates GC progression through its impact on metabolic pathways, suggesting its potential as a therapeutic target for GC treatment.

Background: Colorectal mucinous adenocarcinoma (MAC) shows heterogeneous outcomes after curative resection, and the prognostic value of lymphovascular invasion (LVI) remains unclear. This study evaluated the association of LVI with clinicopathological features, overall survival (OS), and disease-free survival (DFS) in patients with colorectal MAC. Methods: This retrospective cohort study included 2,391 adults with stage I–III pathologically confirmed colorectal MAC who underwent curative resection across 21 hospitals in China between 2016 and 2021. Patients were excluded if they had a mucinous component Results: Among 2,391 patients, 1,397 (58.4%) were male, 994 (41.6%) were female, and 1,231 (51.5%) had stage III disease. LVI was detected in 541 patients (22.6%). LVI positivity was significantly associated with poor differentiation, advanced T stage, N stage, and TNM stage (all Pvs. 86.5%, Pvs. 86.3%, PConclusions: In patients with MAC after curative resection, LVI was associated with more advanced pathological features and independently predicted poorer OS and DFS. Routine assessment of LVI may improve postoperative risk stratification and help identify patients who require closer surveillance.

We aimed to examine the panoramic cellular composition and spatial structure of clinical samples from nonalcoholic fatty liver disease-associated hepatocel

The emerging concept of PANoptosis—a lytic cell death pathway integrating apoptosis, pyroptosis, and necroptosis—presents avenues for cancer immunotherapy, yet its therapeutic exploitation remains limited by undefined molecular sensors and induction strategies. Here, we report a tumor-targeting nanozyme, Hemin-His-Mn, that concurrently activates retinoic acid-inducible gene I–mediated PANoptosome assembly and catalyzes reactive oxygen species amplification to achieve precision PANoptosis induction. Mechanistically, Hemin-His-Mn binds to retinoic acid-inducible gene I and alleviates its autoinhibition, initiating PANoptosome formation through the orchestrated recruitment of cell death executioners, thereby identifying retinoic acid-inducible gene I as a master PANoptosis sensor. In parallel, Hemin-His-Mn exerts peroxidase-like activity to generate cytotoxic reactive oxygen species surges, facilitating complete execution of PANoptosis. This dual mechanism promotes potent immunogenicity by releasing damage-associated molecular patterns and enhancing antigen presentation, ultimately eliciting robust T cell–mediated antitumor immunity. In multiple male mouse preclinical models, Hemin-His-Mn reprograms the tumor immune microenvironment and synergizes with immune checkpoint inhibitors. Our study introduces a retinoic acid-inducible gene I–targeting nanotechnology platform that redefines strategies for PANoptosis induction, provides mechanistic insights into PANoptosome assembly, and offers a clinically translatable modality for enhancing cancer immunotherapy.

The clinical application of targeted therapy and immune checkpoint inhibitors (ICIs) has significantly improved the survival prognosis of patients with hepatocellular carcinoma (HCC). However, due to the high heterogeneity of HCC, the response rate to immunotherapy is still low, and there is an urgent need to identify reliable biomarkers and potential therapeutic targets to improve the therapeutic benefit. In this study, a patient-derived xenograft (PDX) model of HCC was constructed to compare and analyze the tumor tissues of the immunotherapy responder group and the non-responder group. RNA sequencing and proteomics combined analysis found that histone H3K9 trimethyltransferase SETDB2 was highly expressed in the non-responder group. Functional experiments showed that SETDB2 deficiency could significantly inhibit tumorigenesis, enhance CD8⁺ T cell infiltration, and improve the immune microenvironment. Further mechanistic studies found that SETDB2 shut down the chromatin structure of the promoter region of the splicing factor SRSF1 through H3K9me3 modification, inhibiting its expression, thereby leading to a decrease in the proportion of functional spliceosomes of the immune regulatory factor SHP-1. After the activity of SHP-1 was weakened, the JAK/STAT3 signaling pathway was continuously activated, leading to an enhanced tumor immunosuppressive phenotype. SETDB2 overexpression also promoted the polarization of tumor-associated macrophages M2 and inhibited the function of effector T cells, leading to a decrease in immunotherapy response. This study systematically revealed that SETDB2 regulates SRSF1 expression through an epigenetic mechanism mediated by H3K9me3, thereby driving the SHP-1 spliceosome deviation, activating STAT3 signaling and reshaping the key pathway of the immune microenvironment. The SETDB2/SRSF1/SHP-1/STAT3 axis plays a core role in HCC immune escape, providing a new perspective on the mechanism of resistance to immunotherapy in liver cancer, and providing a theoretical basis and potential biomarkers for the combined epigenetic targeted intervention strategy of ICIs.

Gastric cancer is a leading cause of cancer-related death, particularly in East Asia, yet its genetic basis remains incompletely understood. Using genome-wide association study data from BioBank Japan, we show that gastric cancer shares significant genetic associations with 25 other phenotypes, most notably cardiovascular conditions such as angina pectoris and myocardial infarction. Mendelian randomization supports a causal role of these traits in gastric cancer risk. Multitrait analysis of GWAS reveals a novel pleiotropic locus at 12q22 (rs12814712) that is shared between gastric cancer and cardiovascular traits. Functional experiments demonstrate that the risk allele at this locus reduces transcriptional activity and downregulates the expression of nearby genes, particularly VEZT. In gastric cancer cells, overexpression of VEZT and NR2C1 suppress proliferation and migration, whereas their knockdown promotes malignancy. Our analysis identifies rs12814712 as a novel susceptibility locus for gastric cancer and underscores its regulatory role in disease-related gene networks.

Polyethylene terephthalate (PET), one of the most widely produced plastics used in food packaging, has emerged as a pervasive source of microplastic exposure in humans, with recent evidence confirming its presence in the human stomach. However, the biological consequences of PET nanoplastics (PET-NPs) on gastric carcinogenesis remain largely unexplored. In this study, we systematically investigated the effects of PET-NPs on gastric cancer progression and the underlying molecular and immunological mechanisms. PET-NPs were readily internalized by gastric cancer cells, leading to enhanced cell proliferation, migration, and resistance to oxaliplatin, accompanied by suppression of apoptosis and immunogenic cell death. In vivo validation using a mouse subcutaneous tumor model further demonstrated that PET-NPs significantly promoted tumor growth. Integrated mechanistic analyses combining transcriptomics, network toxicology and western blotting revealed that PET-NPs exhibited strong binding affinity to tumor necrosis factor-α (TNF-α), resulting in inhibition of the downstream JAK1/STAT1 signaling pathway. Moreover, PET-NPs profoundly remodeled the tumor immune microenvironment by promoting M2 macrophage polarization, reducing CD8+ T cell infiltration, upregulating immune checkpoint molecules TIGIT and PD-1, and suppressing key antitumor cytokines, including IFN-γ and TNF-α. Collectively, these findings demonstrate that PET-NPs act as a previously underrecognized environmental risk factor that accelerates gastric cancer progression through direct molecular interference and immune suppression, highlighting the potential public health implications of chronic microplastic exposure.

Colorectal mucinous adenocarcinoma (MAC), a distinct subtype of adenocarcinoma (AC) characterized by extracellular mucus production. However, the specific regulatory role of mucus production in MAC development remains underexplored. In this study, scRNA-seq analyses revealed that L1TD1 expression was significantly greater in MAC than in adjacent noncancerous tissues. L1TD1 is an RNA-binding protein that has been reported to regulate mRNA stability and stemness-associated transcriptional programs in cancer cells. Further experiments confirmed that L1TD1 expression was elevated in MAC compared to normal tissues and L1TD1 promoted mucus production and accelerated tumor cell proliferation and metastasis. Mechanistically, further analysis revealed the RNA recognition motif (RRM) domain of L1TD1 binds to the 3′ untranslated region (3’-UTR) of ABCC3 mRNA, thus increasing its stability. In addition, ABCC3 inhibition reversed L1TD1 overexpression-induced mucus production and MAC progression. Collectively our findings demonstrate that L1TD1 binds to the GUGU motif within ABCC3 mRNA and upregulates ABCC3 expression, which subsequently activates the MAPK signaling pathway and promotes mucin production and accelerates MAC progression. These results also provide essential evidence for investigating the mechanisms of mucus production and tumor progression in MAC.

Background: In recent years, the incidence of early upper gastric cancer has increased, leading to a wider adoption of proximal gastrectomy (PG) as a possible treatment option. PG is preferred over total gastrectomy (TG) due to its superior postoperative nutritional status and improved surgical safety. However, PG is associated with a considerable risk of anastomosis‐related complications, such as gastroesophageal reflux and anastomotic stenosis, which limit its widespread application. Methods: We conducted a narrative review of comparative studies, prospective studies and retrospective study, that described reconstructive techniques after PG. End‐points of interest were incidence of reflux esophagitis, anastomotic stenosis, time of follow‐up, nutritional parameters. Results: Esophago‐gastrostomy, the simplest reconstruction method, was associated with highest reflux rates of 18%–55% and stenosis rates of 1.1%–27.8%. Anti‐reflux modifications such as side‐overlap, double‐flap technique (DFT) and gastric tube lowered reflux rate distinctly, especially DFT, lowered reflux rates to 2%–16.7%. But DFT carried a 4%–26.3% stenosis risk and longer operative time. Jejunal interposition (JI) gave 2.1%–100% reflux rates and 0%–31.8% stenosis, yet required three anastomoses and limited endoscopic surveillance. Double‐tract reconstruction (DTR) achieved the promising anti‐reflux outcome, with preserved duodenal passage. However, it may increase surgery costs and prolong surgical time. Conclusion: Our findings provide a solid foundation for reconstruction methods selection that enhance postoperative quality of life and highlight future directions for improving PG outcomes. DTR and DFT, currently offer the best balance between reflux control and anastomotic stenosis after PG. Prospective clinical research and innovation are expected to further improve these techniques and may discover an optimal universal approach to address long‐term challenges.