Lei Fu

Background: Sepsis remains a leading cause of mortality in intensive care units, with endotoxemia-induced hepatic inflammation being a major contributor to multiorgan failure. Bromodomain and extraterminal domain (BET) proteins are key epigenetic regulators of inflammation. While the BET inhibitor JQ1 shows protective effects in sepsis models, its toxicity limits translational application. NHWD-870, a next-generation BET inhibitor with improved potency and safety, has not been evaluated in septic liver injury. Methods: Eight-week-old male C57BL/6 mice were challenged with lipopolysaccharide (LPS) to induce endotoxemia and treated with NHWD-870 1 hour before LPS challenge. Survival rate was assessed and 0.5mg/kg was selected as the optimal dose. Liver injury and inflammation were assessed by histopathology, serum biochemistry, ELISA, RT-qPCR, and immunohistochemistry. In vitro, primary mouse hepatocytes (PMHs) and bone marrow-derived macrophages (BMDMs) were stimulated with LPS to examine NHWD-870 effects on cytokine production and macrophage polarization. Results: NHWD-870 improved survival in lethal LPS challenge and attenuated LPS induced ALT/AST elevations and hepatic inflammatory infiltration. Serum and hepatic IL6, TNFα, and MCP1 were reduced after NHWD-870; IL6 suppression at 12 h exceeded JQ1. NHWD-870 decreased hepatic macrophage and neutrophil infiltration and no obvious histopathological abnormalities were observed in the major organs at the active dose. In vitro, NHWD-870 dose dependently reduced LPS induced cytokine expression in PMH and BMDM and inhibited macrophage M1 polarization (CD86, iNOS). BRD4 and STAT1 expression increased after LPS; NHWD 870 suppressed both. Conclusion: NHWD-870 ameliorates endotoxemia-associated hepatic inflammation and improves survival in mice, at least in part via suppression of BRD4-STAT1 signaling and inhibition of macrophage M1 polarization. Further preclinical development is warranted.

Background: The prognosis of acute-on-chronic liver failure (ACLF) is impaired by etiology heterogeneity across regions. Currently, prognostic models incorporating nutrient anabolism–related indicators for patients with hepatitis B virus (HBV)–associated ACLF are lacking. Objectives: This study aimed to construct a nomogram that incorporates nutrition-related indexes alongside traditional predictors to estimate 12-week mortality in HBV-ACLF. Methods: We retrospectively analyzed adult patients with HBV-ACLF treated at our department between May 2020 and December 2021. A total of 242 HBV-ACLF patients were enrolled and categorized into survivor (n = 174) and progression (n = 68) groups. Independent prognostic factors were identified using logistic regression analysis and incorporated into a nomogram. Nomogram performance was evaluated in terms of discrimination, calibration, and clinical utility, with internal validation using bootstrap resampling. Results: Patients in the progression group were older, more prone to hepatorenal syndrome and spontaneous peritonitis, and had lower levels of prothrombin activity, L3 skeletal muscle index and ceruloplasmin (all p < 0.05). These six independent predictors were incorporated into the nomogram, which demonstrated superior discrimination ability, with an area under the receiver operating characteristic curve of 0.95, enabling accurate identification of patients at high risk of short-term mortality. The Hosmer–Lemeshow test confirmed excellent calibration, decision curve analysis confirmed the clinical benefit, and bootstrap validation confirmed the robustness. Conclusions: The developed nomogram, incorporating nutritional status, may provide complementary information to support short-term risk stratification and clinical decision-making in patients with HBV-ACLF awaiting liver transplantation.

Excessive inflammation and immune activation are strongly associated with unfavorable outcomes and elevated mortality rates in hepatitis B virus (HBV)‐related acute‐on‐chronic liver failure (ACLF). However, the role of the C‐reactive protein to lymphocyte ratio (CLR) as a prognostic inflammatory biomarker in multiple diseases is rarely mentioned in HBV‐ACLF. This investigation aimed to assess the utility of the CLR and additional parameters in identifying high‐risk progression in HBV‐ACLF patients. A cohort of 639 hospitalized patients diagnosed with HBV‐ACLF based on the APASL criteria was divided into two cohorts: 447 cases in the training set and 192 cases in the validation set. Logistic regression analysis was employed to identify the XY‐model. The results of multiple factor analysis showed that the incidence of liver cirrhosis, age, CLR, serum total bilirubin, calcium, prothrombin activity, and alpha fetoprotein affect the prognosis of HBV‐ACLF. CLR emerged as a significant independent risk factor for disease progression in patients with ACLF (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01–1.04, p < 0.05). The novel model based on seven predictors could accurately predict short‐term mortality in patients with HBV‐ACLF, which is promising for guiding clinical management and addressing the etiological differences in Asian populations.

Background: Functional cure of chronic hepatitis B (CHB) can be achieved with appropriate antiviral treatment. However, few studies have evaluated the added benefits of achieving functional cure. We aimed to conduct a quantitative analysis of the health-related quality of life (HRQoL) of CHB patients who achieved functional cure to provide evidence for economic analysis. Methods: We conducted a cross-sectional study in five provinces in China in 2021. The study population was recruited in hospitals and divided into three groups: functional cure, antiviral treatment, and healthy control group. Data were collected through face-to-face interviews using the Short Form-36 version 2. Results: 497 participants (163 with functional cure, 192 with antiviral treatment, and 142 with healthy control) were used in this study. The eight scale scores (physical function, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health) and two summary scores (physical composite and mental composite) in the functional cure and healthy control groups were similar. Compared to the healthy control group, the general health scores in the functional cure group were worse with −0.052 (95% CI: −0.094, −0.010), and the antiviral treatment group had significantly worse scores with −0.127 (95% CI: −0.170, −0.083). The antiviral treatment group had lower vitality scores (β = −0.048, 95% CI: −0.089 to −0.007) and MCS scores (β = −0.023, 95% CI: −0.042, −0.003, p = 0.022) compared to the healthy control. The mental composite summary scores of all groups were >50 (p > 0.05). Conclusions: Health-related quality of life decreases with CHB disease progression. The results indicate that functional cure is associated with HRQoL levels comparable to those of the healthy population, both on the physical and psychological aspect, reinforcing the clinical value of this therapeutic goal.

Sexually transmitted infections (STIs), including HIV/AIDS, remain a major global public health issue for women of childbearing age (WCBA). However, comprehensive data on their epidemiological and economic burden and long‐term trends in this population are limited. This study aims to systematically assess the global, regional, and national burden and temporal trends of HIV/AIDS and other significant STIs among WCBA from 1990 to 2021, and to evaluate the associated economic burden in 2021. Data were obtained from the Global Burden of Disease Study 2021 to estimate the incidence, prevalence, mortality, and disability‐adjusted life years (DALYs) for HIV/AIDS and other STIs across 204 countries or territories. Temporal trends were assessed using estimated annual percentage change (EAPC). An age‐period‐cohort model was applied to estimate relative risks, and frontier analysis was used to determine efficiency in resource utilization. The economic burden in 2021 was estimated using an indirect cost approach. In 2021, an estimated 287 million incident cases of HIV/AIDS and other STIs occurred globally. Since 1990, new HIV/AIDS cases have declined by 25.1%, and the age‐standardized incidence rate (ASIR) decreased by 46.5%, while the age‐standardized prevalence rate (ASPR), age‐standardized mortality rate (ASMR), and age‐standardized DALYs rate (ASDR) increased. In contrast, other STIs saw a 54.3% rise in incident cases, with slight increases in ASIR and ASPR, and decreases in ASMR and ASDR. The burden was highest in low sociodemographic index (SDI) regions and declined with increasing SDI. Sub‐Saharan Africa remained the most affected region. Global direct healthcare spending on HIV/AIDS and other STIs among WCBA reached $2.46 billion in 2021, with high‐SDI countries accounting for the majority. Low‐SDI countries, despite high disease burdens, contributed minimally to global spending. From 1990 to 2021, the burden of HIV/AIDS and other STIs among WCBA increased significantly, with notable regional disparities. Sub‐Saharan Africa carries a disproportionately high burden of HIV/AIDS and other STIs yet receives insufficient global attention. Low‐SDI populations face greater disease burdens but benefit from less healthcare investment, underscoring the urgent need to strengthen STIs‐specific prevention, treatment, and health education in these regions.

Background: Mucormycosis is a rare, rapidly progressive fungal infection with a high mortality rate. However, clinical data of mucormycosis patients, especially those related to adverse outcomes in China, remain limited.Objective: To enhance understanding of the clinical characteristics of different infection site mucormycosis and identify the factors associated with adverse outcomes.Methods: A 14‐year retrospective study was conducted at a tertiary care hospital in China. Patients were categorised based on the site of infection and clinical outcomes.Results: From 2010 to 2024, 32 cases of mucormycosis were identified. Among these, pulmonary mucormycosis (PM) was the most common infection site, followed by disseminated mucormycosis. All patients had underlying comorbidities, predominantly chronic lung disease (37.5%) and diabetes mellitus (34.3%). All received pharmacological treatment, most commonly amphotericin B; 15.6% of patients additionally underwent surgical intervention. Chest CT findings in PM cases most frequently revealed bilateral involvement (68.8%) and cavitation (43.8%). Diagnosis was primarily based on metagenomic next‐generation sequencing (mNGS, n = 14) and histopathological examination (n = 11). Adverse outcomes were observed in 46.9% of patients and were significantly associated with corticosteroid or immunosuppressant use, COVID‐19 co‐infection, disseminated disease, thrombocytopenia, hypoalbuminemia, elevated aspartate aminotransferase (AST), increased incidence of complications, and ICU admission (all p < 0.05).Conclusion: Pulmonary mucormycosis was the predominant subtype in this cohort and was frequently associated with chronic lung disease and diabetes. The high incidence of adverse outcomes highlights the necessity for early diagnosis, prompt antifungal therapy, and aggressive management of complications to improve patient survival.

Chronic liver diseases (CLDs) are prevalent globally. The purpose of the current study was to elucidate the regulatory mechanisms underlying the pathophysiological processes in CLDs. Using the GEO database, we identified cysteine and methionine metabolism as a commonly enriched pathway in some CLDs. We then confirmed that hepatic cystathionine γ-lyase (Cth), a key enzyme in this pathway, was significantly downregulated in some CLDs in humans and rodent models. Cth-deficient mice exhibited hepatic necroptosis, inflammation and mitochondrial impairment. Omics revealed methionine cycle dysregulation and reduced betaine, a methionine cycle metabolite. Betaine supplementation rewired the methionine cycle, and alleviated necroptosis, inflammation and mitochondrial impairment. Dysregulation of fatty acid β-oxidation, glycolysis and lipid biosynthesis caused by Cth deficiency was improved by betaine. Cth deficiency decreased Pparα, Nrf2, Pgc-1α, and Srebf2 (the transcription factors linked to mitochondria function and metabolism) expression while increasing Irf8 and Irf9, changes reversed by betaine. Histone methylation (H3K9me3, H3K27me3, H3K79me3) decreased, and acetylation (H3K27ac) increased with Cth deficiency, which betaine corrected. Irf8 and Irf9 and Ppara and Ppargc1a expression were regulated by H3K27me3 and H3K79me3 in hepatocytes, respectively. Our study indicates that CTH is the key factor for maintaining hepatocyte function and survival through homeostasis of the methionine cycle and immediately highlights a new potential target of hepatic protection therapy for some CLDs.

Cholestasis, characterized by impaired bile flow, leads to significant hepatic dysfunction and poses a clinical challenge. This study investigated cellular communication networks and molecular mechanisms underlying cholestasis using advanced single-cell and transcriptomic sequencing. Data from the GEO database, including single-cell sequencing (GSE237622) and transcriptome datasets (GSE206364, GSE183754), were analyzed to identify biomarkers and therapeutic targets. Lasso regression highlighted IL32, CRIP2, ANXA2, and VWF as key genes, supported by immune infiltration, functional enrichment, and drug repurposing analysis via the Connectivity Map (CMap) database. Expression of these genes was validated in liver tissue from 13 cholestatic liver disease (CLD) patients and 10 controls. Single-cell sequencing identified 534 cell-type-specific markers, with significant upregulation of IL32, CRIP2, ANXA2, and VWF in CLD patients, particularly in endothelial cells near liver sinusoids and periportal areas. Their expression correlated with serum ALT and AST levels, reflecting disease severity. Drug repurposing analysis identified dexamethasone, fenofibrate, promazine, and SB-590,885 as potential therapies. This study identifies IL32, CRIP2, ANXA2, and VWF as pivotal biomarkers and therapeutic targets for cholestasis, offering new avenues for targeted interventions.

Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), involves hepatic lipid accumulation, inflammation, and fibrosis. It can progress to cirrhosis or hepatocellular carcinoma without timely treatment. Current treatment options for MASH are limited. This study explores the therapeutic effects of fluorofenidone (AKF-PD), a novel small-molecule compound with antifibrotic and anti-inflammatory properties, on MASH in mouse model. Mice fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) were treated with AKF-PD, resulting in reduced serum ALT, AST, hepatic lipid accumulation, liver inflammation, and fibrosis. Network pharmacology and RNA-sequencing analyses suggested that AKF-PD influenced multiple metabolic, inflammatory, and fibrosis-related pathways. Further experiments verified that AKF-PD activated hepatic AMPK signaling, leading to the inhibition of the downstream SREBF1/SCD1 pathway and the activation of autophagy. Additionally, AKF-PD suppressed the expression of various inflammatory factors, reduced macrophage infiltration, and inhibited NLRP3 inflammasome activation. Moreover, AKF-PD attenuated liver fibrosis by inhibiting TGFβ1/SMAD signaling. In conclusion, this study reveals that AKF-PD effectively decreases hepatic lipid accumulation, liver inflammation and fibrosis in a CDAHFD-induced MASH model, positioning AKF-PD as a promising candidate for the treatment of MASH.