Heat shock protein 90 (HSP90) serves as a central orchestrator of oncogenic protein homeostasis, empowering tumor progression, metastasis, and therapy resistance. However, the clinical translation of HSP90 inhibition has been hampered by challenges such as intrinsic and acquired resistance, a lack of reliable biomarkers, and the toxicity associated with pan-inhibitors. This review comprehensively dissects these challenges and presents the evolving landscape of strategies to overcome them. We systematically catalog the development of over 20 representative HSP90 inhibitors, from classical N-terminal ATP-competitive agents to novel C-terminal and middle-domain binders, highlighting their distinct mechanisms and the rise of subtype-selective compounds designed to enhance therapeutic windows. Beyond monotherapy, we emphasize the paradigm shift towards combination regimens, detailing synergistic effects with chemotherapy, targeted agents, and immunotherapies that resensitize tumors to treatment. Critically, we explore the diagnostic frontier, reviewing how radiolabeled HSP90 inhibitors (e.g., [¹²⁴I]PU-H71 and [¹⁸F]San A derivatives) enable non-invasive tumor detection and patient stratification through positron emission tomography (PET). Finally, we chart the future course of the field, underscoring how precision medicine approaches—guided by biomarker identification and liquid biopsy—coupled with nanotechnology-driven delivery systems, are poised to unlock the full potential of HSP90-targeted cancer theranostics. This synthesis provides not only a mechanistic overview but also a strategic roadmap for the next generation of HSP90-directed oncology research.

The inflammation-immune-nutrition score (IINS) plays a significant role in predicting survival outcomes across various cancers. The study aimed to comprehensively evaluate the prognostic value of IINS in different cancers through a meta-analysis. A systematic literature search was conducted in PubMed, Embase, Web of Science and Scopus databases for eligible studies published up to March 15, 2026. Pooled hazard ratios (HRs) with 95

Short chain fatty acids (SCFAs), the primary metabolites produced by gut microbiota, play an essential role in maintaining hepatic homeostasis. Recent studies have indicated that Cadmium (Cd) not only directly triggers oxidative stress and mitochondrial damage, but also indirectly exacerbates Cd-induced hepatotoxicity by depleting SCFAs, thereby compromising their protective effects on the liver. Cd alters gut microbiota composition by reducing the Firmicutes/Bacteroidetes ratio and depleting SCFAs-producing bacteria such as Lachnospiraceae and Ruminococcaceae, thereby decreasing SCFAs production. It induces intestinal epithelial necrosis and downregulates tight junction proteins (occludin, claudin-1, and ZO-1), which impairs SCFAs absorption, compromises intestinal barrier function, and promotes the translocation of endotoxins to the liver via the gut-liver axis. Cd further disrupts SCFAs metabolism and promotes lipid accumulation by suppressing β-oxidation related genes and proteins, thereby synergistically exacerbating hepatic damage. We also highlight the potential of exogenous SCFAs supplementation to alleviate Cd toxicity by restoring microbial balance, elevating SCFAs levels, and enhancing barrier integrity. These insights offer a novel perspective and strategic basis for dietary interventions in preventing and treating heavy metal related liver diseases.

Transfer RNA-derived small RNAs (tsRNAs) have been implicated in tumor progression and immune regulation in recent years. However, the specific role of tRNA halves (tiRNAs), a subclass of tsRNAs, in modulating immunotherapy response remains unexplored. In this study, 5’-tiRNAGly levels were examined in gastric cancer (GC) patients and found to be upregulated, especially in non-responders to anti-PD-1 therapy. Elevated 5’-tiRNAGly levels were also associated with diminished oxoglutarate dehydrogenase-like (OGDHL) expression. Further exploration revealed that 5’-tiRNAGly bound to DLST and promoted OGDHL destabilization, whereas targeted inhibition of 5’-tiRNAGly restored OGDHL stability through succinylation at lysine 910, enhanced tricarboxylic acid (TCA) cycle activity, and reduced glutamine-derived metabolic reprogramming. Additionally, 5’-tiRNAGly was found to decrease the activity of α-ketoglutarate dehydrogenase and inhibit succinylation of histone H3 at lysine 79 (H3K79suc), thereby downregulating PD-L1 transcription and reducing therapeutic responsiveness to PD-1 inhibitors. Conversely, restoration of this epigenetic modification upon 5’-tiRNAGly inhibition facilitated PD-L1 transcription, thereby sensitizing tumors to anti-PD-1 therapy. Our findings indicate that targeting 5’-tiRNAGly may represent a promising strategy to enhance responsiveness to anti-PD-1 therapy in GC patients.

Background and Objectives:Various lumen-apposing metal stents (LAMSs) were used for pancreatic fluid collection (PFC) drainage for many years. The structural design of LAMS needs to be improved to reduce the occurrence of adverse events. This trial assessed the efficacy and safety of a novel modified LAMS for the drainage of PFCs. Methods:This open-label, multicenter, prospective trial was done at 11 tertiary care hospitals. This study enrolled patients (18-75 years old) with confirmed diagnosis of PFC with cyst diameter no less than 6 cm. Novel LAMS (Micro-Tech Co, Ltd, Nanjing, China) was used. The primary end point was the 1-month postoperative drainage success rate. The secondary end points were technical success rate and adverse events. This study is registered with Chictr.org.cn, ChiCTR2000039955. Results:Between December 9, 2020, and December 27, 2021, 100 patients with PFC were assessed for eligibility, and 94 patients met the criteria and agreed to participate in the trial. The median size of PFC cyst was 11.23 ± 3.84 cm. The drainage success rate was 90.48% (95% CI, 83.6%-97.3%) and achieved the prespecified target value of 75% (P < 0.0001). In subgroup analysis, the clinical success rates of pancreatic pseudocyst (PPC) and walled-off necrosis (WON) were 95.45% and 85%, respectively (P = 0.143). The overall technical success rate was 98.94%. Postoperative early adverse events occurred in 57 (60.64%) of 94 patients, and late adverse events were encountered in 16 (17.02%) of 94 patients. The overall rate of serious adverse event (bleeding-related death) was 2.13% (2/94). Patients with WON had a significantly higher rate of early adverse events compared to those with PPC (77.78% vs. 44.90%, P = 0.001). Conclusions:The novel LAMS used in this trial was technically feasible, efficient, and safe for the treatment of PFCs. Comparable with WON, the usage of LAMS in PPC achieved a high drainage success rate and acceptable adverse events.

BackgroundEvidence regarding the hepatotoxic effects of co-exposure to multiple heavy metals in the general middle-aged and older adults population remains limited. This study aimed to investigate the association between heavy metal mixtures and liver function in the population of Northwest China, with key findings supported using an animal model.MethodsWe conducted a cross-sectional study involving 451 participants from the Dongdagou Xinglong cohort. Concentrations of heavy metals and liver function indices were measured. Multiple linear regression, Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS), and quantile-based g-computation (Qgcomp) regression were employed to evaluate the combined effects of co-exposure to multiple heavy metals on liver function. A sub-chronic cadmium (Cd) exposure rat model was further established to validate population-based findings.ResultsMultiple linear regression analysis revealed that blood Cd was positively correlated with GGT (β = 0.236), TBA (β = 0.162), ALT (β = 0.142) and AST (β = 0.114), while negatively correlated with DBil (β = −0.207), TBil (β = −0.166) and IBil (β = −0.157) (all P < 0.05). Similarly, other heavy metals also exhibited significant associations with liver function indicators. BKMR analysis showed that heavy metal mixture exposure was positively associated with ALT, AST, ALP, GGT, CHE, and TBA, but negatively associated with TBil, DBil, and IBil; WQS regression indicated that positive associations between the metal mixture and GGT as well as CHE; and the Qgcomp model demonstrated that the metal mixture was positively associated with ALT, GGT, and TBA, and negatively associated with TBil, DBil, and IBil. Notably, all three statistical models consistently identified Cd as the factor associated with liver function biomarkers. Furthermore, animal experiments provided experimental evidence consistent with the human findings: Cd exposure led to elevated serum GGT and ALP levels and induced histopathological alterations in the liver. Transcriptomic sequencing suggested that hepatic lipid metabolism pathways may be involved in Cd-induced liver injury.ConclusionsOverall, our study shows that co-exposure to heavy metals is associated with liver function biomarkers in middle-aged and older adults, with Cd identified as the predominant factor associated with liver function biomarkers.

Background:Diffuse large B-cell lymphoma (DLBCL) is a malignant tumor with moderate-high aggressiveness and heterogeneity. In recent years, several studies have shown that tumor cell-derived exosomes are involved in the process of tumorigenesis and progression through microRNA (miRNA). Therefore, exosomal miRNAs are potential diagnostic and prognostic biomarkers for cancer. The aim of this study was to explore the potential of a set of exosomal miRNAs in peripheral blood as noninvasive biomarkers for the auxiliary diagnosis of DLBCL. Methods:Exosomes were collected from the peripheral blood of three DLBCL patients and two healthy controls, and miRNA expression was detected using high-throughput sequencing technology. MiRNAs were analyzed by Weighted Gene Co-expression Network Analysis to screen out the correlated model genes of DLBCL, subsequently, receiver operating characteristic (ROC) curves were constructed to verify the diagnostic efficacy of this group of miRNAs and validation was performed using the GSE171272 dataset. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed for the target genes of hsa-miR-589-5p, hsa-miR-4728-3p and hsa-miR-5006-3p. Results:We identified eight exosomal miRNAs with the potential to differentiate DLBCL patients from healthy controls. ROC curves were generated using the GSE171272 dataset to assess the diagnostic performance of these miRNAs. Among them, hsa-miR-589-5p, hsa-miR-4728-3p, hsa-miR-5006-3p, hsa-miR-30b-5p, hsa-miR-4323, hsa-miR-484, hsa-miR-4500, and hsa-miR-99a-5p exhibited an AUC greater than 0.8. Specifically, the area under the curve (AUC) of hsa-miR-589-5p, hsa-miR-4728-3p and hsa-miR-5006-3p were both 1.00 [95% confidence interval (CI): 0.93-1.00]. Conclusions:In this study, exosomal miRNAs contribute to the diagnosis of DLBCL and may serve as non-invasive diagnostic biomarkers for DLBCL. This offers novel perspectives on utilizing exosomal miRNAs for the early identification of DLBCL and their potential clinical application. However, given the small size of the discovery cohort, these estimates are presented as exploratory and should be confirmed in larger independent cohorts.

This study aimed to identify a novel microRNA (miRNA)-related circulating biomarker that is easily accessible for clinical use and can dynamically monitor the biological characteristics of diffuse large B-cell lymphoma (DLBCL). We analyzed miRNA expression profiles in DLBCL from the Gene Expression Omnibus (GEO) (GSE171272 and GSE173080) and The Cancer Genome Atlas (TCGA). The immune microenvironment and immune-related gene differences associated with hsa-miR-23a-5p were assessed through the single-sample gene set enrichment analysis and CIBERSORT. Gene set enrichment analysis identified expression trends related to hsa-miR-23a-5p. The 50% inhibitory concentration of chemotherapy agents was estimated for hsa-miR-23a-5p. Potential miRNA targets were identified using TargetScan, miRWalk, and RNA22, and validated with miRTarBase, DIANA-TarBase, and NPInter. Gene functions and associated pathways were analyzed through Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. Protein-Protein Interaction networks were built using Cytoscape. SNRPD1-related analysis was conducted using TCGA and GEO data. Hsa-miR-23a-5p was significantly overexpressed in the tumor tissues and serum exosomes of patients with DLBCL. The expression levels of hsa-miR-23a-5p were associated with distinct prognostic outcomes, immune landscapes, chemoresistance, and biological processes, serving as potential risk factors. The target gene SNRPD1 was an independent prognostic factor significantly associated with patient survival. This study identifies hsa-miR-23a-5p and its target SNRPD1 as potential prognostic factors for DLBCL. Specifically, the overexpression of hsa-miR-23a-5p in serum exosomes of patients with DLBCL suggests that it could serve as a convenient, non-invasive biomarker for clinical evaluation of DLBCL. However, further research and validation are necessary to confirm these findings.

Effective therapies for liver fibrosis are lacking. The RNA-binding protein Lin28A is upregulated in human cirrhotic and mouse fibrotic livers, where it localizes to activated hepatic stellate cells (HSCs). HSCs-specific overexpression of Lin28A worsened carbon tetrachloride (CCl4)-induced fibrosis in mice. In LX-2 and primary mouse HSCs, Lin28A knockdown suppressed activation and induced hallmarks of ferroptosis, including mitochondrial damage, lipid peroxidation, and glutathione depletion. Mechanistically, Lin28A repressed the maturation of let-7 microRNAs, leading to increased expression of its target, high-mobility group AT-hook 2 (HMGA2). HMGA2, alongside hypoxia-inducible factor-1α (HIF-1α), contributed to the downregulation of the ferroptosis defense proteins SLC7A11 and GPX4. Notably, the anti-fibrotic effects of the Lin28A inhibitor C1632 were dependent on ferroptosis induction, as co-treatment with ferrostatin-1 reversed its impact on HSCS activation and death. In vivo, C1632 treatment alleviated CCl4-induced liver fibrosis. These results identify Lin28A as a regulator of HSCS ferroptosis and a potential target for anti-fibrotic therapy.

OBJECTIVE:To assess the potential causal relationships of the oral microbiome with the risks of oral cancer, oropharyngeal cancer, and tongue cancer using two-sample Mendelian randomisation (MR) analysis, while distinguishing these from reverse causal effects of the cancers on microbial abundance. METHODS AND MATERIALS:Using single-nucleotide polymorphisms as instrumental variables, we applied the MR inverse-variance-weighted approach to evaluate the effects of the dorsal-tongue and salivary microbiomes on oral, oropharyngeal, and tongue cancers. Analyses were conducted with the R package TwoSampleMR, leveraging genome-wide association study (GWAS) summary statistics from CNGBdb, the FinnGen consortium, and other sources. Sensitivity, heterogeneity, and pleiotropy assessments were performed. Additionally, reverse MR sensitivity analyses were conducted to explore the possible causal influence of cancers on the oral microbiota. RESULTS:Using a single nucleotide polymorphism (SNP) significance threshold of p 5 × 10-6, our large-scale MR study revealed genetically supported causal relationships between microbial taxa derived from saliva and the tongue and the risk of oral, oropharyngeal, and tongue cancers. Integrating these results, we found that both 's Veillonella_rogosae_mgs_2008' and 's unclassified_mgs_1048' conferred a reduced risk of oropharyngeal and tongue cancers. Sensitivity analyses based on heterogeneity tests and pleiotropy evaluations further corroborated the robustness of our findings, lending additional credibility to the conclusions. CONCLUSION:This study leveraged large-scale publicly available genetic data and identified significant causal relationships between the oral microbiota and cancers of the oral cavity, oropharynx, and tongue. Reverse MR analyses indicated that oral and tongue cancers may in turn alter the abundance of specific oral microbes, suggesting a potential bidirectional causal loop. Future work should integrate metagenomic data to further validate these microbiota-cancer associations.

To compare the clinical outcomes of ERCP combined with laparoscopic LC using both one-step and two-step approaches for the treatment of cholecystocholedocholithiasis, and to investigate the optimal timing for performing LC within two weeks after ERCP. The clinical data of 520 patients with cholecystocholedocholithiasis who were treated with ERCP and LC between January 2018 and December 2023 were retrospectively analyzed. Those who underwent ERCP and LC simultaneously with a single anesthesia constituted the one-step group (n = 60), whereas those who had ERCP and LC in separate sessions were categorized as the two-step group (n = 460), patients in the one-step approach group and the two-step approach group were matched using 1:4 propensity score matching (PSM). After PSM, the one-step approach group comprised 58 cases, and the two-step approach group comprised 218 cases. The 460 patients in the two-step group were further divided into three subgroups: ≤24 h group (n = 186), 24–72 h group (n = 187), and 72 h-2w group (n = 87). We compared general patient information, preoperative laboratory indexes, imaging data, intraoperative conditions, and postoperative outcomes between the one-step and two-step groups, as well as among the three subgroups of the two-step method. An ordinal logistic regression model was used to evaluate the effect of ERCP-related complications occurring before LC on LC timing, and a sensitivity analysis was performed to validate the robustness of the findings. The one-step approach group exhibited significantly shorter hospital stays (7 vs. 9 days, P < 0.001) and lower hospital costs (29,703 vs. 33039rmb, P = 0.002) than the two-step approach group; The 72 h-2w group exhibited a longer length of stay (11vs.8vs.9days, P < 0.001), higher hospitalization costs (36810vs.32264vs.31556rmb, P < 0.001), a greater overall complication rate after ERCP (18.4

Background:MSCs are an important component of the TME and play a key role in tumor progression. Based on existing in vitro studies, this research aims to investigate the role of mesenchymal stem cells in the EMT of HNSCC and its related mechanisms. Methods:According to the PRISMA guidelines, we systematically searched PubMed, Embase, and Web of Science databases for relevant in vitro studies up to May 6, 2024. Two trained researchers independently performed literature screening, data extraction, and quality assessment, with cross-checking of results. Any disagreements were resolved through discussion or by consulting a third party. Meta-analysis was conducted using Stata 17 software. Results:A total of 8 in vitro studies were included, involving OSCC, NPC, and TSCC. The meta-analysis results indicate that MSC intervention may be associated with a reduction in the expression of epithelial markers and an increase in mesenchymal markers and related transcription factors in cancer cells, implying a potential role for MSCs in promoting EMT in vitro. Furthermore, a preliminary review of the underlying molecular mechanisms suggests that this process may involve the potential regulation of multiple signaling pathways, including NF-κB, PI3K/Akt/mTOR, IL-6R/JAK/STAT3, CXCL8/CXCR2, TGF-β/Smad, and FGF19-FGFR4. Conclusions:The existing in vitro evidence suggests that mesenchymal stem cells may exhibit a potential to promote EMT in HNSCC, potentially regulating tumor progression through multiple signaling pathway networks and providing new potential targets for future therapies targeting the TME. However, more high-quality, standardized in vivo and in vitro studies are needed to further validate the related mechanisms and therapeutic potential.

tsRNAs are a kind of small non-coding single-stranded RNA, which play an important role in many kinds of tumours. Previous studies have identified that tRF-31-U5YKFN8DYDZDD can be used as a novel tumour biomarker for the diagnosis and prognosis of gastric cancer (GC). In this study, we further explored the regulatory effect of tRF-31-U5YKFN8DYDZDD on tumour biological function in GC cells and related regulatory mechanisms. Inhibition of tRF-31-U5YKFN8DYDZDD can inhibit the proliferation, invasion, migration and angiogenesis of GC cells, while overexpression of tRF-31-U5YKFN8DYDZDD has the opposite effect. BMPER was shown to be a direct target of tRF-31-U5YKFN8DYDZDD in GC. Furthermore, the cytological effects of stable overexpression of BMPER were similar to the inhibition of tRF-31-U5YKFN8DYDZDD. And the attenuation of BMPER expression rescued the tRF-mediated promotion of GC cells. WB showed that up-regulation of tRF-31-U5YKFN8DYDZDD could increase the phosphorylation level of ERK and Smad1/5, and promote the expression of epithelial mesenchymal transition (EMT) and matrix metalloproteinases. Animal experiments in vivo show that down-regulation of tRF-31-U5YKFN8DYDZDD can effectively inhibit tumour growth. These data suggest that tRF-31-U5YKFN8DYDZDD is a new tumour-promoting factor and may be a potential new therapeutic target for GC.

[This corrects the article DOI: 10.3389/fimmu.2025.1705852.].

The gut immune microenvironment and the liver engage in intricate information exchange via the gut–liver axis. The disruption of these interactions plays a pivotal role in the formation and exacerbation of pathological damage to the liver. The gut immune microenvironment is not an independent layer of the gut barrier; rather, it permeates and regulates all other barrier functions, serving as the core coordinator. Disruption of the immune microenvironment in the gut–liver axis drives progression across the full disease spectrum—from steatosis to hepatitis, fibrosis, and even liver cancer—through the continuous influx of immune-stimulatory signals that overwhelm the liver’s intrinsic immune regulatory mechanisms. Dysfunction of innate immunity components, amplification of inflammatory factors and key cellular signaling pathways, activation of adaptive immune T cells, and systemic effects mediated by liver-derived inflammatory factors collectively form a disordered immune microenvironment. This damages the intestinal barrier and exacerbates liver disease via the gut–liver axis, leading to further intestinal injury, thus establishing a self-reinforcing vicious cycle. Current therapeutic strategies based on modulating the gut–liver axis microenvironment remain limited, yet studies have demonstrated that suppressing gut immune cells, cytokines, and signaling pathways can help delay liver disease progression. Hopefully, future combined, precise, and cutting-edge gut immunotherapies will provide more effective strategies for liver disease treatment.

OBJECTIVES:Complex chronic conditions (CCCs) are increasingly prevalent in the PICU. Identifying high-risk patterns of CCC and comorbidities is essential for patient risk stratification and targeted management. In this study, we aimed to describe the distribution and patterns of CCCs among children admitted to our tertiary PICU in China and to identify the types and combinations of conditions associated with a higher risk of adverse outcomes. DESIGN:Retrospective cohort study, January 2020 to February 2025. SETTING:Single center, at a tertiary referral PICU in Central-Southern China. PATIENTS:Children older than 28 days, up to 18 years old. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:CCCs were defined according to the Pediatric Complex Chronic Conditions Classification System Version 2. Of 9589 PICU admissions, 49% had one or more CCCs. Admissions with CCCs accounted for 69.8% of the adverse outcomes, 70.8% of in-hospital deaths, 58% of multiple organ dysfunction cases, and 57.6% of total patient days. Admissions with multiple CCC diagnoses were associated with higher odds of adverse outcomes compared with admissions with a single CCC diagnosis ( p < 0.0001). Transplantation and metabolic CCCs were associated with greater odds of adverse outcomes (odds ratios [OR], 6.06 and 5.27, respectively; p < 0.05). The most common co-occurring CCC categories were malignancy and hematologic/immunologic disorders. Among the most frequent combinations, the co-occurrence of metabolic and malignancy CCC was associated with greater odds of adverse outcomes (OR, 8.54 [95% CI, 4.48-16.29]). Admission with CCC was associated with pneumonia and sepsis ( p < 0.05). CONCLUSIONS:In our 2020-2025 experience, admission of patients with CCCs accounted for most of the adverse PICU outcomes. The odds of adverse outcomes varied across CCC types and combinations. Hence, incorporating CCCs into a stratified management approach across our healthcare system may support more effective planning and delivery of care.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly linked to systemic metabolic disturbances and features a lipid-driven cascade that promotes hepatic inflammation and fibrosis. Choline insufficiency contributes to disease advancement by altering phospholipid turnover and redox homeostasis; however, its spatial and temporal regulatory roles throughout MASLD progression remain insufficiently defined. A 10-week high-fat, choline-deficient (HFCD) mouse model was established, and liver pathology was evaluated at weeks 6, 8, and 10. Time-resolved assessments combined untargeted metabolomics, magnetic resonance imaging-proton density fat fraction (MRI-PDFF), serum biochemistry, histological staining, immunofluorescence, and transmission electron microscopy to characterize dynamic alterations in lipid metabolism, redox status, inflammation, and fibrogenesis. The HFCD diet produced a clear temporal sequence of liver injury. Steatosis, phosphatidylcholine depletion, and early antioxidant loss appeared by week 6. By week 8, mitochondrial structural damage and pronounced cytokine elevation were evident. At week 10, collagen deposition and α-SMA activation signaled fibrotic progression. Metabolomics indicated significant disruptions in pathways related to ATP-binding cassette (ABC) transporters, one-carbon metabolism, and the tricarboxylic acid (TCA) cycle. Using integrated analytical strategies, this study suggests that choline deficiency may be associated with a time-dependent pathological cascade in MASLD, beginning with phospholipid destabilization and extending to altered mitochondria-endoplasmic reticulum crosstalk at mitochondria-associated membranes, alongside amplified oxidative-inflammatory responses, which collectively may contribute to progressive fibrogenesis as the disease advances.