Maternal sepsis carries a high risk of progression to septic shock. However, existing risk stratification tools, such as qSOFA and the Sepsis in Obstetrics Score, perform suboptimally in pregnant and postpartum populations, and no simple model specifically predicts progression from sepsis to septic shock. This study aimed to identify variables associated with septic shock in maternal sepsis, characterize infection sources and pathogens, and develop and internally validate a practical predictive model. A retrospective cohort study was conducted on 139 pregnant and postpartum women with sepsis admitted to a single tertiary center between January 2016 and July 2025. The primary outcome was septic shock within 72 h of sepsis diagnosis, and predictors were collected at the time of diagnosis. Patients were randomly split into training (70

Cellular senescence plays a critical role in physiological and pathological processes. This study aims to elucidate the contribution of cellular senescence-related genes to disease etiology. We investigated a cohort study of 439,501 individuals, which included 22 cancers and 9 non-cancer diseases. We found that HLA-E and HLA-G-associated senescence in epithelial and immune cells were specific oncogenic factors for prostate and lung cancers. MAP2K4 was implicated as a risk factor for breast cancer, while ZFP36L1 and STAT3 were associated with a reduced risk of inflammatory bowel disease (IBD). Notably, ETS2-mediated inhibition of the senescence-associated secretory phenotype (SASP) was associated with decreased disease risk. Furthermore, single-cell level analysis confirmed that the dynamics of these marked gene expressions in immune cells was related to reduced disease risk, while upregulation in epithelial cells correlated with increased disease risk. In parallel, co-localization analyses corroborated these associations, explaining potential regulatory mechanisms underlying disease risk variants. These findings enhance our understanding of how cellular senescence works on disease susceptibility and provide potential targets for therapeutic interventions and precision medicine approaches.

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of liver diseases worldwide and imposes an increasingly heavy burden on society. After years of research, salvianolic acid B (Sal B), the main component of traditional Chinese medicine Salvia miltiorrhiza, exhibits significant efficacy in alleviating fatty liver; however, its precise mechanism of action against MASLD remains unclear. PURPOSE:This study aimed to investigate the underlying pharmacological mechanism of Sal B in treating MASLD, using both in vivo and in vitro models. STUDY DESIGN:A systematic pharmacology approach combining multi-species phenotypic screening with proteomics and molecular target verification was employed to elucidate the mechanism of Sal B against MASLD. METHODS:MASLD models were established in thioacetamide‑treated zebrafish, MCD diet‑fed mice, and oleate/palmitate‑exposed AML12 hepatocytes. The therapeutic effects of Sal B were assessed by histology, proteomics, Seahorse metabolic analysis, calcium imaging, flow cytometry, and molecular binding assays such As spr, CETSA, and competitive labeling. The involvement of Piezo1 and the C215 residue was examined by siRNA‑mediated knockdown, NEM competition, and expression of wild‑type versus C215S mutant protein. RESULTS:Sal B treatment was associated with reduced hepatic lipid accumulation, inflammation, oxidative stress, and energy metabolism disturbances in all three models. Proteomic analysis suggested modulation of a PPAR‑centered metabolic network. Sal B appeared to interact with the Piezo1 extracellular domain, and the C215S mutation markedly decreased this interaction. In Piezo1‑overexpressing HEK293T cells, Sal B attenuated YODA1‑induced Ca²⁺ influx; this effect was not observed following NEM pretreatment or Piezo1 knockdown. Sal B also reduced YODA1‑elicited mitochondrial Ca²⁺ overload and ROS production in AML12 cells, effects that were less evident when Piezo1 was knocked down. Moreover, Piezo1 knockdown alone produced changes in PPAR‑related genes similar to those induced by Sal B, and adding Sal B to knockdown cells did not lead to further alterations. CONCLUSION:The available evidence suggests that Sal B can inhibit Piezo1 channel activity, possibly through interaction with cysteine 215 in its extracellular domain, and that this may contribute to alleviation of mitochondrial Ca²⁺ overload, oxidative stress, and metabolic dysregulation in MASLD models. Importantly, the identification of C215 as the binding site is based on computational prediction and SPR assays using the truncated extracellular domain; direct functional confirmation with full‑length C215S mutant protein remains to be performed. These findings point to C215 as a candidate binding residue for Sal B and support further investigation of Piezo1‑targeted strategies for MASLD.

The Warburg effect drives cancer cells to rely preferentially on glycolysis, resulting in diminished mitochondrial oxidative phosphorylation (OXPHOS). This metabolic phenotype limits the ability of excess copper (Cu) ions to trigger cuproptosis in dysfunctional mitochondria, leading to suboptimal therapeutic outcomes. Therefore, remodeling tumor energy metabolism to counteract the Warburg effect represents a pivotal strategy to enhance cuproptosis efficacy. Herein, we developed a Cu(I)-stabilized metal-organic framework nanoplatform (CuTz-1) encapsulated by Azurin (CuTz-1@Azurin) as a cuproptosis sensitizer. Mechanistically, Azurin increases p53 protein levels by intercepting MDM2-mediated ubiquitin-proteasome degradation. Elevated p53 subsequently inhibits pyruvate kinase M2 (PKM2) activity, suppressing glycolysis, while simultaneously promoting mitochondrial OXPHOS-collectively shifting cellular metabolism from glycolysis toward mitochondrial respiration and sensitizing tumor cells to Cu-induced proteotoxic stress. In addition, CuTz-1@Azurin triggers oxidative stress via reactive oxygen species (ROS) generation and glutathione (GSH) depletion, which act together with p53-mediated apoptosis to suppress tumor growth. Meanwhile, the oxidation of Cu(I) to paramagnetic Cu(II) enables real-time monitoring of the therapeutic process by magnetic resonance imaging (MRI). Both in vitro and in vivo results demonstrate good antitumor performance of CuTz-1@Azurin. This study highlights the potential of Azurin-mediated metabolic regulation as a promising strategy to potentiate cuproptosis for combined cancer therapy.

Acute pancreatitis (AP), an acute inflammatory condition commonly encountered in patients admitted to intensive care unit, is mainly caused by gallstones, alcohol abuse, or hyperlipidemia. Traditional views focus on single-etiology AP; however, Chinese studies have shown that mixed-etiology AP (two or more etiologies) is also fairly common. Comparing the clinical characteristics of AP with different etiologies is crucial for guiding personalized treatment strategies and understanding disease severity and recurrence patterns. However, few studies have explored the prognostic differences between single-etiology and mixed-etiology AP; moreover, the predictors of disease severity in mixed-etiology AP cases remain unclear. This retrospective cohort study compared severity and prognostic outcomes between single-etiology AP and mixed-etiology AP and established a predictive model for severe AP (SAP) in mixed-etiology AP patients. For this purpose, patients diagnosed with AP from January 2019 to December 2023 at the First Affiliated Hospital of Xi’an Jiaotong University were recruited. Of 630 AP patients, 18.3

BACKGROUND Early diagnosis of upper gastrointestinal bleeding (UGIB) relies on invasive endoscopy and laboratory tests, which carry procedural risks and diagnostic delays. The pathophysiological relationship between bowel sounds (BSs) as a noninvasive monitoring metric and UGIB remains to be elucidated. AIM To investigate the feasibility of BS acoustic signatures as UGIB screening biomarkers, analyze their pathological correlations with hematological indices, and construct a machine learning-assisted diagnostic model. METHODS A prospective study enrolled 40 UGIB patients (endoscopy-confirmed within 24 hours) and 40 age-/sex-matched healthy controls. BS signals were recorded at the right lower umbilical quadrant using a G-200 device (60 seconds/subject, 4 kHz sampling). After denoising via variational mode decomposition, 78-dimensional features were extracted across four domains: Time-domain, frequency-domain, time-frequency domain, and nonlinear dynamics. Weighted feature importance was calculated using an integrated strategy and gradient-optimized feature subsets were used to train four classifiers: Support vector machine, random forest, logistic regression, and K-nearest neighbor. SHapley Additive exPlanations analysis was conducted on the features of the optimal model. Model performance was evaluated by fivefold cross-validation. Spearman's correlation analysis was performed to assess key BS features against red blood cell count, hemoglobin, hematocrit, C-reactive protein (CRP), and high-sensitivity CRP. RESULTS The support vector machine classifier with 25-feature subsets achieved optimal performance (area under the curve > 0.89), significantly outperforming other models. Acoustic feature importance analysis identified band_Energy and Mel-frequency cepstral coefficient variance as core biomarkers (cumulative contribution > 60%). Key pathological correlations included: (1) Significant negative correlations between spectral centroid and red blood cell count/hemoglobin/hematocrit (P < 0.01); (2) Positive correlation between wavelet entropy and these hematological parameters (P < 0.05), suggesting multiscale microcirculatory flow fluctuations; and (3) Positive wavelet energy correlations with CRP/high-sensitivity-CRP (P < 0.05). CONCLUSION Multidimensional BS features enable noninvasive UGIB screening. Their strong correlation with anemia/inflammation indicators reveals an acoustic-hemato-physiological coupling mechanism, providing a novel paradigm for early UGIB monitoring.

The digital divide may exacerbate healthcare disparities among vulnerable populations. However, evidence regarding its impact on healthcare utilization among chronic liver disease (CLD) patients remains limited, particularly using comprehensive multidimensional assessments. This study aimed to investigate the association between multidimensional digital divide and healthcare service utilization among Chinese adults with CLD. We analyzed data from 405 CLD patients (aged ≥ 45 years) from the China Health and Retirement Longitudinal Study (CHARLS) Wave 5 (2020). Digital divide was assessed through a comprehensive framework incorporating access, usage, and application dimensions, measured by internet use, device diversity, usage breadth, WeChat use, and mobile payment capability. Healthcare service utilization was defined as any hospitalization in the past year or outpatient visit in the past month. Multivariable logistic regression models, subgroup analyses, and sensitivity analyses including alternative outcome definitions, quartile analysis, and propensity score matching were performed. Among participants (median age 58.2 years, 51.6% male), 53.1% experienced digital divide. Healthcare service utilization was significantly lower among those with digital divide (hospitalization: 13.5% vs. 27.4%, P = 0.001; outpatient visits: 21.9% vs. 56.8%, P < 0.001). After full adjustment, standardized digital divide dimensions showed strong associations with healthcare utilization: access dimension (OR = 2.89, 95%CI: 2.18–3.84), usage dimension (OR = 3.13, 95%CI: 2.34–4.17), application dimension (OR = 1.67, 95%CI: 1.33–2.10), and overall score (OR = 3.63, 95%CI: 2.66–4.94). Significant age interactions were observed (P < 0.001). Sensitivity analyses confirmed robustness, with propensity-matched analysis showing OR = 2.63 (95%CI: 1.53–3.75). Multidimensional digital divide substantially impacts healthcare service utilization among CLD patients. Targeted interventions addressing digital disparities are needed to ensure equitable healthcare access in the digital era.

BACKGROUND:Our prior studies revealed that mixed Gram-negative and Gram-positive bacterial infections in acute cholangitis are more severe and have higher mortality rates. This study aims to identify the risk factors and predictors for such infections in acute cholangitis. METHODS:A retrospective review of patients meeting selection criteria based on blood and bile culture results for different pathogenic bacteria was conducted, with comprehensive clinical and laboratory data analyzed. RESULTS:A total of 503 patients were enrolled. Mixed bacterial growth developed in 134 patients (26.6%) while non-mixed bacterial growth developed in 369 patients (73.4%). Mixed bacterial infection was identified as an independent risk factor for in-hospital death ((odds ratio (OR), 5.23 [95% confidence interval (CI) 1.55-17.60], p=0.008). Cardiovascular disease (OR 1.75 [95% CI 1.12-2.73], p=0.015), chronic renal insufficiency (OR 4.68 [95% CI 1.07-20.46], p=0.040), biliary stent placement (OR 3.12 [95% CI 1.54-6.42], p=0.002), surgical incision and drainage history (OR 1.98 [95% CI 1.12-3.49], p=0.019), and biliary anastomosis(OR 9.53 [95% CI 1.83-49.76], p=0.007) were independently associated with mixed bacterial infection in multivariate analysis. The ROC (receiver operating characteristic) curves for subjects with mixed bacterial infections using Acute Physiology And Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment score (SOFA) were 0.721 (95% CI, 0.67-0.77, P<0.001) and 0.718 (95% CI, 0.67-0.77, P<0.001), respectively. CONCLUSIONS:In acute cholangitis, cardiovascular disease, chronic renal insufficiency, surgical incision and drainage history, biliary stent placement and biliary anastomosis were independent risk factors for mixed bacterial infection.

SLC38A1 has been identified as a carcinogenic factor in the progression of colorectal, gastric, pancreatic, and other cancers. However, its involvement in lung adenocarcinoma (LUAD) remains unexplored in the literature. The expression levels, diagnostic relevance, and clinical significance of SLC38A1 in LUAD were evaluated using data from the TCGA, XENA, and LCE databases, along with validation in samples from 10 LUAD patients at our hospital. Prognostic nomograms and risk models based on SLC38A1 were constructed. The functional roles and mechanisms of SLC38A1 in LUAD were investigated through CCK-8 assays, migration and invasion assays, Western blotting, GO and KEGG pathway analyses, and correlation analysis to explore its relationship with the immune microenvironment. SLC38A1 was overexpressed in both unpaired and paired LUAD samples, with a marked increase in early-stage LUAD. Overexpression of SLC38A1 correlated with diagnostic accuracy and poor overall survival (HR = 1.53; 95

Hypoxia, defined as a condition of insufficient tissue oxygenation, is recognized as a key characteristic of solid tumors and is closely associated with their aggressive phenotypic traits. The cellular response to hypoxia is regulated by hypoxia-inducible factors (HIFs), a family of transcription factors that promote the transcription of gene products involved in driving tumor progression, including processes such as proliferation, angiogenesis, metastasis and drug resistance. In the field of cancer therapeutics, targeting the HIF pathway has emerged as a promising strategy, and the Food and Drug Administration approval in 2021 of Welireg, a novel agent designed to target HIF-2α for the primary treatment of von Hippel-Lindau syndrome, has further validated its favorable prospects in tumor therapy. Gastric cancer (GC) continues to pose a notable global health challenge, as it accounts for ~1 million new cases of cancer each year and is responsible for >650,000 mortalities annually. Currently, a range of therapeutic approaches are available for patients diagnosed with GC, yet the 5-year survival rate remains suboptimal for those with advanced-stage disease. The present review summarizes the regulatory and target roles of HIFs in GC, thus providing references for GC treatment and emphasizing the potential of HIF-targeted therapies to disrupt cancer-associated signaling pathways.

INTRODUCTION:The impact of continuous renal replacement therapy (CRRT) with oXiris hemofilter (oXiris CRRT) on sepsis outcomes remain controversial. We aimed to investigate the association between the oXiris CRRT and subsequent outcomes in adult patients with septic shock. METHODS:This single-center, retrospective cohort study included adult patients with septic shock, who were admitted to the intensive care unit (ICU) of our tertiary referral hospital between 2019 and 2023, and underwent at least one CRRT session. Patients were categorized into two groups based on the initially hemofilter used (oXiris group vs. M100 group). A 1:1 propensity score matching was performed to compare the primary outcome 28-day vasopressor-free days. RESULTS:Of 465 patients who met all eligibility criteria, 69 cases in the oXiris group were matched with 69 individuals in the M100 group. Compared with the M100 group, the use of oXiris CRRT was associated with longer 28-day vasopressor-free days (24 vs. 19 days, P = 0.04), shorter CRRT duration (72 vs. 117 h, P = 0.03), and a greater reduction in SOFA scores (-2 vs. 1, P = 0.004). However, competing risk analysis indicated no significant between-group difference in the cumulative incidence of vasopressor weaning after accounting for the competing risk of ICU mortality. Furthermore, no significant between-group differences were observed in changes in lactate, PCT, or IL-6 levels, fluid balance, ICU or hospital length of stay (LOS), or short-term mortality. CONCLUSIONS:In this cohort of septic shock patients undergoing CRRT, unadjusted analyses demonstrated potential improvements in hemodynamic stability and organ function following oXiris therapy. Nevertheless, these preliminary signals were not confirmed by competing risk analysis of the primary outcome. Therefore, the clinical impacts of oXiris CRRT observed in the present study must be viewed cautiously, well-designed prospective investigations are warranted to verify its definitive therapeutic value.

Background: Zhuang medicine has long been used for the clinical management of liver cancer (LC); however, its underlying therapeutic mechanisms remain largely unelucidated. This study aimed to identify bioactive compounds within Zhuang medicine formulations and investigate their potential mechanisms of action against LC. Methods: Differentially expressed genes (DEGs) in LC were identified using the Gene Expression Omnibus (GEO) database. High-frequency, robust herbs employed in LC treatment were screened utilizing established network pharmacology approaches, and their primary active ingredients were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. LC-associated gene datasets were integrated from GeneCards, Online Mendelian Inheritance in Man (OMIM), PharmGKB, Therapeutic Target Database (TTD), and DrugBank databases. Key candidate genes were pinpointed through the integration of Weighted Gene Co-expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) network analysis. Molecular docking simulations using AutoDock software assessed potential interactions between the identified active ingredients and their putative targets. The therapeutic effects of diosgenin, a prioritized compound, were further validated through in vitro experiments utilizing Hepa1-6 murine hepatoma cells. Results: Screening identified ten frequently prescribed Zhuang herbs and eight core active ingredients. Molecular docking analyses revealed that diosgenin exhibits favorable binding affinity with key targets CAT, NR1I2 (PXR), and NR3C2 (MR). In vitro validation demonstrated that diosgenin dose-dependently and significantly inhibited the proliferation and migration of Hepa1-6 cells. Furthermore, Western blot and immunofluorescence analyses confirmed that diosgenin treatment significantly reduced the expression levels of metastasis-associated proteins MMP2 and vimentin, as well as the proliferation marker PCNA. Conclusion: This study provides a systematic investigation into the potential active ingredients and molecular mechanisms underpinning Zhuang medicine's efficacy against liver cancer. Our findings strongly implicate diosgenin as a promising therapeutic candidate for LC and establish a crucial theoretical foundation for the further development of anticancer agents derived from Zhuang medicinal resources.

Prognostic stratification after curative-intent resection for pancreatic ductal adenocarcinoma (PDAC) remains challenging. We performed a systematic review and meta-analysis to identify prognostic factors associated with overall survival (OS) in resected PDAC. PubMed, Embase, Web of Science and the Cochrane Library were searched for studies reporting hazard ratios (HRs) for OS after PDAC resection. Observational studies and randomized trials reporting univariable or multivariable HRs for clinicopathologic and treatment variables were eligible, regardless of treatment sequence. Pooled HRs with 95

4114 Background: Hepatocellular carcinoma (HCC) with lung metastasis carries a dismal prognosis, and effective systemic treatments remain limited. Bispecific antibodies targeting multiple immune checkpoints have emerged as promising therapeutic strategies. This study assessed the efficacy and safety of QL1706, a PD-1/CTLA-4 bispecific antibody, in combination with bevacizumab in patients with HCC and lung metastases. Methods: This was a secondary analysis of a multicenter, phase Ib/II clinical trial. Eligible patients with unresectable, advanced HCC and confirmed lung metastases received QL1706 (5.0 or 7.5 mg/kg, cohort A) or QL1604 (PD-1 antibody, 200 mg, cohort B) plus bevacizumab every three weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: In cohort A, 15 patients were included in this analysis. At a median follow-up of 19.2 months, the ORR was 53.3% (95% CI, 26.6–78.7) and the DCR was 73.3% (95% CI, 44.9–92.2). Median PFS was 9.9 months (IQR, 1.6–NE), with a 1-year PFS rate of 46.7%, and the 2-year OS was 66.7%. Among the 7 patients with measurable lung target lesions, the ORR was 71.4% (95% CI, 29.0–96.3), including 2 complete responses. In cohort B, 5 patients were included, with a median follow-up of 23.7 months. The ORR was 20.0% (95% CI, 0.5–71.6) and the DCR was 60.0% (95% CI, 14.7–94.7). Treatment-related adverse events occurred in 93.3% of patients in cohort A and 100.0% in cohort B, with grade ≥3 TRAEs observed in 53.3% and 40.0% of patients, respectively. Most adverse events were manageable, and no treatment-related deaths were reported. Conclusions: QL1706 plus bevacizumab demonstrated promising antitumor activity and a manageable safety profile in patients with HCC and lung metastases. The high response rate observed in lung lesions highlights the potential of intensified immunotherapy combined with anti-VEGF therapy for this subgroup, warranting further validation in phase III trials. Clinical trial information: NCT05603039 . Treatment-emergent adverse events of QL1706 / QL1604 and bevacizumab. All grades Grade ≥ 3 Cohort A (N = 15) Cohort B (N = 5) Cohort A (N = 15) Cohort B (N = 5) TEAEs 15 (100.0) 5 (100.0) 10 (66.7) 4 (80.0) irAEs 11 (73.3) 0 2 (13.3) 0 TRAEs 14 (93.3) 5 (100.0) 8 (53.3) 2 (40.0) Associated with QL1706 / QL1604 14 (93.3) 5 (100.0) 6 (40.0) 2 (40.0) Associated with bevacizumab 14 (93.3) 5 (100.0) 8 (53.3) 3 (60.0)

Kirsten rat sarcoma virus (KRAS) mutations comprise approximately 85% of rat sarcoma virus (RAS) alterations and occur in more than 90% of pancreatic ductal adenocarcinomas (PDACs) and over 40% of colorectal cancers (CRCs). Although KRAS-G12C inhibitors have transformed a target long considered undruggable, most gastrointestinal (GI) tumours harbour non-G12C alleles and remain constrained by intrinsic, acquired and adaptive resistance and by an immunosuppressive tumour microenvironment (TME). This review synthesizes allele- and disease-specific biology and epidemiology; delineates immune vulnerabilities created by KRAS-driven remodelling of the TME; and appraises emerging modalities with near-term clinical relevance, including next-generation allele-specific and pan-KRAS inhibitors, RAS degraders, KRAS-directed T cell receptor (TCR) therapies and neoantigen vaccines. We integrate genomic, signalling and clinical evidence to define primary, acquired and adaptive resistance archetypes and map them to rational combination strategies. By translating rapidly evolving biology into practice-oriented guidance, this review outlines opportunities to extend benefit beyond KRAS-G12C, overcome resistance, inform trial design and improve real-world decision-making for patients with KRAS-mutant GI malignancies.

Total antioxidant capacity (TAC) is a key parameter for overall antioxidant evaluation in food, but its efficient measurement remains challenging. In this study, ball milling modified biochar (BM-BC) nanozyme was prepared via pyrolysis followed by ball-milling treatment and its physicochemical properties were fully characterized to explore the catalytic oxidation mechanism of BM-BC, reminiscent of oxidase. Compared with pristine biochar, BM-BC demonstrated significantly enhanced oxidase-like catalytic activity, effectively oxidizing 3,3′,5,5′-tetramethylbenzidine (TMB) to blue-colored ox-TMB. The oxidase-mimicking mechanism of newly prepared BM-BC nanozyme was further elucidated and revealed that BM-BC generated ROS including •OH, •O2-, and 1O2 for mediating TMB oxidation, in which the persistent free radicals (PFRs) on BM-BC played a critical role. Owing to the antioxidant activity on TMB oxidation, ascorbic acid was employed as the representative antioxidant for colorimetric TAC detection. The method exhibited a linear detection range of 10~100 μM with a limit of detection (LOD) of 2.4 μM. Furthermore, the BM-BC/TMB reaction-based colorimetric assay was successfully applied for TAC determination in beverages and fruits.

Background: Liver fibrosis (LF) is a common pathological process in the progression of multiple chronic liver diseases to cirrhosis, affecting millions of people worldwide annually. The incomplete understanding of its mechanisms has led to a lack of clinically effective therapeutic options. ErTao decoction (ETD, (sic)(sic)(sic)), a derivative combining the components of Erchen Decoction and Taohong Siwu Decoction, is rooted in the traditional Chinese medicine theory of "phlegm-dampness-blood stasis". However, the precise mechanism by which ETD exerts its therapeutic effects in LF remains unclear. Purpose: The purpose of study was to investigate the protective effect of ETD and elucidate its underlying molecular mechanism on LF. Methods: In this study, we employed a multifaceted approach to evaluate the effects of ETD on LF. We used H&E staining, Sirius red staining, immunofluorescence, immunohistochemical analysis, and Western blotting to assess the protective effects of ETD in a CCl4-induced fibrosis mouse model. In vitro validation was conducted using macrophages and hepatic stellate cells to further elucidate the mechanisms involved. STING-deficient mice were used to assess its regulatory effects on liver injury, inflammatory and activation through immunohistochemical staining and Western blotting. Furthermore, UHPLC-HRMS detection and computer-aided drug analysis were employed to identify and validate potential effective components of ETD for responsible for its therapeutic effects in treating LF. Results: In our in vivo and in vitro experiments, we found that ETD effectively reduced collagen fiber deposition and alleviated LF pathological changes by inhibiting macrophage inflammatory activation and suppressing NLRP3 and STING signaling. Notably, STING deficiency exhibited a protective effect against liver tissue injury and inhibited inflammatory activation of hepatic macrophages in LF model mice. Additionally, comprehensive analysis of the active ingredients in ETD strongly suggested that Naringin served as a pivotal bioactive constituent within ETD responsible for modulating STING signaling. Conclusions: Our study highlighted the protective effects of ETD on LF by inhibiting STING-mediated macrophage activation and NLRP3 inflammasome signaling. Notably, Naringin might serve as a promising novel STING

Background & Aims: Hepatocellular carcinoma (HCC) displays heterogeneous responses to lenvatinib, with tumor microenvironment (TME) stiffness emerging as a key resistance modulator. This study investigates how tumor peripheral stiffness governs lenvatinib efficacy via mitochondrial fission/mitophagy and evaluates matrix-targeting combination therapies. Methods: Clinical HCC tissues underwent stiffness measurement (atomic force microscopy [AFM]/rheometry) and survival correlation analyses. In vitro, cells grown on soft vs. stiff hydrogels (5 vs. 15 kPa) were assessed for their lenvatinib response, mitophagy, and mitochondrial fission 1 (FIS1)–trimethylation of histone H3 lysine 27 (H3K27me3) regulation. Subcutaneous xenografts received collagenase-lenvatinib combination therapy. Results: Elevated tumor peripheral stiffness, quantified by AFM and rotational rheometry, was significantly associated with HCC recurrence. Patients with stiff peripheries exhibited reduced recurrence-free survival (p <0.05), correlating with upregulated mitophagy markers (Parkin and FIS1) and diminished H3K27me3 in high-stiffness human HCC tissues (p <0.0001). In vitro, HCC cells on stiff matrices (15 kPa) showed attenuated lenvatinib-induced apoptosis (TUNEL: p = 0.0003 vs. soft 5 kPa) and preserved mitochondrial membrane potential (JC-1: p = 0.0004), concomitant with fragmented mitochondria driven by FIS1 upregulation via H3K27me3 depletion at its promoter (chromatin immunoprecipitation: p <0.0001). FIS1 knockdown reversed mitochondrial fragmentation (p <0.001) and resensitized cells to lenvatinib. Stiffness amplified cytoprotective mitophagy under lenvatinib stress, evidenced by enhanced LC3/TOM20 colocalization (p = 0.0008) and mitochondrial Parkin accumulation. In vivo, collagenase-mediated matrix softening synergized with lenvatinib, suppressing tumor growth (volume: p <0.001; weight: p <0.001) while reducing FIS1/Parkin expression and augmenting apoptosis. Conclusions: Tumor peripheral stiffness drives lenvatinib resistance in HCC via H3K27me3-mediated FIS1 upregulation, triggering mitochondrial fission and cytoprotective mitophagy to evade drug-induced apoptosis. Targeting matrix stiffness (via collagenase-mediated softening) synergizes with lenvatinib to overcome microenvironment-driven resistance, providing a novel mechanoadjuvant strategy for HCC therapy. Impact and implications: This study shows that tumor peripheral matrix stiffness reduces lenvatinib sensitivity in HCC by enhancing FIS1-dependent mitophagy, explaining therapeutic response heterogeneity. These findings are clinically relevant, highlighting tumor stiffness as a potential biomarker for lenvatinib resistance and mitophagy as a targetable pathway. Clinically, stiffness assessments (e.g. imaging/biopsy) could be used to stratify patients for personalized treatment. Combining lenvatinib with matrix-softening agents or mitophagy inhibitors could improve efficacy. However, translational potential requires validation in larger cohorts and development of non-invasive stiffness measurement methods, given challenges associated with the clinical application of current invasive techniques or collagenase-based preclinical models.

Chronic kidney disease (CKD) is one of the most common clinical kidney diseases, during which fibrosis may play a significant role. Hepatic fibrosis index such as AST/ALT-to-platelet ratio index (AARPRI) and fibrosis-4-index (FIB-4) are novel noninvasive index for evaluating hepatic fibrosis, but the relationship between AARPRI and CKD is unclear. Our objective is to determine if AARPRI has predictive value for CKD and to optimize its predictive value. The current cross-sectional study in the National Health and Nutrition Examination Survey (NHANES) was conducted between 2013 and 2018 to calculate the AARPRI index among adult participants. An independent association between AARPRI and CKD was investigated by a generalized linear regression model. The predictive value of AARPRI for CKD was analyzed by ROC analysis. Then a new model was constructed through machine learning to improve the predictive performance of the two indicators, after that a more suitable model for the prediction of CKD was constructed. The study involved 10425 patients in total, of whom 1983 (19.022%) had CKD for the diagnosis (Fig. 1). After adjustment for covariates, generalized linear regression analysis revealed that a high AARPRI level was associated with increased likelihood of CKD (β = 0.107, 95% CI: 0.09, 0.124 P < 0.001) (Fig. 2). The predictive value of AARPRI (AUC = 0.591) for CKD was smaller than that of FIB-4 (AUC = 0.706) (Fig. 3). After machine learning, we built a new model to improve the diagnostic value of AARPRI (AUC = 0.754) and FIB-4 (AUC = 0.762) for CKD respectively (Figs 4–7). Our results suggested that when AARPRI index was less than 1.375, the higher AARPRI levels were associated with the higher CKD prevalence in patients. In addition, the prediction value of the model after comprehensive consideration of glycosylated hemoglobin, blood urea nitrogen and age will be further improved.