Xiaojing Wang

Cancer progression does not occur in isolation: malignant-cell states and fates are shaped by specialized microenvironments, or cancer niches. Within primary tumors, vascular, stromal, immune and neural interactions create local hypoxic, metabolic and mechanical conditions that together influence malignant-cell behavior. These local environments sustain stem-like states, regulate immune surveillance and vascular remodeling, and influence dissemination and treatment response. Tumor-derived extracellular vesicles and other systemic signals connect primary tumors to distant organs, conditioning tissues before tumor-cell arrival and subsequently modulating disseminated tumor-cell seeding, dormancy, reactivation and outgrowth. Cancer niches therefore operate across spatial scales and disease stages, shaping tumor behavior in ways that cannot be explained by tumor-cell-intrinsic properties alone. Advances in single-cell and spatial profiling, organoid systems and intravital imaging are revealing their cellular composition, local architecture and evolution. In this review, we integrate primary, pre-metastatic and metastatic niche biology, examine how local environments evolve and influence one another during cancer progression, compare organ-specific metastatic niches and assess emerging therapeutic strategies. Effective niche-directed therapy will require identifying the interactions that sustain disease, showing that treatment disrupts them and determining which patients are most likely to benefit. Greater spatial, temporal and functional resolution may reveal new therapeutic vulnerabilities and create opportunities to prevent relapse and achieve more durable disease control.

Metabolic dysfunction–associated steatotic liver disease (MASLD) is frequently accompanied by hepatic fibrosis and systemic cardiovascular complications; however, the mechanistic interplay between coagulation abnormalities and disease progression remains poorly defined. Here, analyses of liver tissues and plasma from patients with MASLD, together with complementary mouse models, suggest an important role of immunothrombosis in fibrotic progression. In MASLD mouse models, pharmacological anticoagulation with dabigatran or aspirin attenuates fibrosis but increases systemic bleeding risk, highlighting the need for more selective strategies. Mechanistically, neutrophil extracellular traps (NETs) promote localized fibrin deposition within the hepatic microvasculature, leading to impaired microcirculation and liver sinusoidal endothelial cell (LSEC) capillarization associated with increased Piezo1‐dependent mechanosensation, thereby exacerbating fibrosis. Further investigation identifies neutrophil‐derived fibrinogen‐like protein 2 (FGL2) as a key upstream regulator of NETs formation through interaction with histone deacetylase 11 (HDAC11), promoting histone H3 deacetylation and facilitating PAD4‐mediated citrullination to drive NETs release. Genetic disruption of FGL2 or NETs inhibition restores LSEC fenestration, improves microvascular hemodynamics, and attenuates fibrosis without increasing systemic bleeding risk. Together, these findings define an immunothrombotic axis linking neutrophil‐derived FGL2–HDAC11 signaling to NETs formation and endothelial dysfunction in MASLD, providing mechanistic insight into the interplay between coagulation and metabolic liver disease.

Immunothrombosis, the interplay between immune activation and coagulation, contributes to disease progression in inflammatory disorders. Its role in hepatitis B virus–related acute-on-chronic liver failure (HBV-ACLF) and the involvement of neutrophil extracellular traps (NETs) remain unclear. This study aimed to elucidate NETs-mediated immunothrombosis in HBV-ACLF.

Background Concomitant metabolic dysfunction-associated steatotic liver disease (MASLD) is prevalent in patients with chronic hepatitis B (CHB), yet its impact on liver-related outcomes remains controversial. Although the stimulator of interferon genes (STING) pathway is pivotal in innate immunity, its involvement in CHB-MASLD comorbidity is undefined. Objective We aimed to elucidate the role and mechanism of macrophage STING in CHB-MASLD comorbidity. Design Human and mouse liver tissues were used to assess STING expression levels. Myeloid-specific STING knockout and hepatocyte-specific STING knock-in mice were used to explore the effects of STING in comorbidity. Tohoku Hospital Pediatrics (THP)-1 and HepG2.2.15/HepG2-NTCP co-cultured cells were stimulated with palmitic acid (PA) for 12 hours in vitro for mechanism research. Markers for STING, autophagy and endoplasmic reticulum stress (ERS) were assessed using western blot analysis, immunohistochemistry and immunofluorescence assays. The liver organoids were used for validation. Results CHB-MASLD comorbidity in mice decreased HBV replication but accelerated liver inflammation and fibrosis, linked to aberrant STING upregulation in macrophages. HBV synergised with lipotoxicity to disrupt Rab7 expression and function in macrophages, impairing STING degradation via autophagic-lysosomal and endosomal-lysosomal pathways. Pathological STING accumulation had dual effects: cytosolic STING enhanced antiviral activity (TANK-binding kinase 1-interferon regulatory factor 3-interferon beta) and promoted inflammation (nuclear factor kappa-B/NOD-like receptor family pyrin domain-containing 3 (NLRP3)). Extracellular vesicles transported STING to hepatocytes, triggering ERS (PKR-like endoplasmic reticulum kinase (PERK)-C/EBP homologous protein (CHOP)), further activating NLRP3 and exacerbating injury. Therapeutically, restoring Rab7 facilitated STING degradation, attenuating pathology. Conclusions In CHB-MASLD comorbidity, impaired Rab7 function leads to aberrant STING accumulation in macrophages, suppressing HBV replication but paradoxically accelerating liver disease progression. Targeting Rab7 to degrade excessive STING represents a novel therapeutic strategy.

Background: The fatality rate of hemorrhagic fever with renal syndrome (HFRS), due to hantavirus transmitted by rodents, ranges from 1% to 12%. This study aims to delineate the clinical and laboratory characteristics of HFRS, identify factors associated with disease severity, and construct and validate a nomogram for prognosis prediction of HFRS in the central part of China. Methods: Out of 598 HFRS patients diagnosed via serology tests from four hospitals in Hubei Province, 551 were included. Clinical data were gathered and analyzed, followed by logistic univariate and multivariate analyses to identify independent prognostic factors. A nomogram was developed and validated to forecast the patient’s prognosis. Results: Vaccination led to a notable drop in HFRS incidence from 2018 to 2019, and seasonal trends exhibited bimodal changes with peaks from May to July and November to January. The 30-day mortality rate was 4.17% (23/551). Red blood cell count (RBC), age, two-stage overlap, qSOFA ≥ 2, aspartate aminotransferase (AST), and three-stage overlap were identified as independent prognostic factors. A predictive risk classification system using a nomogram chart was developed, and Kaplan–Meier curves indicated that the new system accurately distinguished 30-day mortality among the three risk groups. Conclusions: The risk score (EASTAR) system demonstrated good predictive performance for prognostic prediction, and it can be applied to quickly screen patients who require ICU admission.

Background and Aims: Gut microbiota plays a prominent role in the pathogenesis of metabolic dysfunction–associated steatotic liver disease (MASLD). IL-33 is highly expressed at mucosal barrier sites and regulates intestinal homeostasis. Herein, we aimed to investigate the role and mechanism of intestinal IL-33 in MASLD. Approach and Results: In both humans and mice with MASLD, hepatic expression of IL-33 and its receptor suppression of tumorigenicity 2 (ST2) showed no significant change compared to controls, while serum soluble ST2 levels in humans, as well as intestinal IL-33 and ST2 expression in mice were significantly increased in MASLD. Deletion of global or intestinal IL-33 in mice alleviated metabolic disorders, inflammation, and fibrosis associated with MASLD by reducing intestinal barrier permeability and rectifying gut microbiota dysbiosis. Transplantation of gut microbiota from IL-33 deficiency mice prevented MASLD progression in wild-type mice. Moreover, IL-33 deficiency resulted in a decrease in the abundance of trimethylamine N-oxide–producing bacteria. Inhibition of trimethylamine N-oxide synthesis by 3,3-dimethyl-1-butanol mitigated hepatic oxidative stress in mice with MASLD. Nuclear IL-33 bound to hypoxia-inducible factor-1α and suppressed its activation, directly damaging the integrity of the intestinal barrier. Extracellular IL-33 destroyed the balance of intestinal Th1/Th17 and facilitated Th1 differentiation through the ST2-Hif1a-Tbx21 axis. Knockout of ST2 resulted in a diminished MASLD phenotype resembling that observed in IL-33 deficiency mice. Conclusions: Intestinal IL-33 enhanced gut microbiota–derived trimethylamine N-oxide synthesis and aggravated MASLD progression through dual regulation on hypoxia-inducible factor-1α. Targeting IL-33 and its associated microbiota may provide a potential therapeutic strategy for managing MASLD.

Non-alcoholic fatty liver disease (NAFLD) is a global health burden closely linked to insulin resistance, obesity, and type 2 diabetes. The complex pathophysiology of NAFLD involves multiple cellular pathways and molecular factors. Nuclear receptors (NRs) have emerged as crucial regulators of lipid metabolism and inflammation in NAFLD, offering potential therapeutic targets for NAFLD. Targeting PPARs and FXRs has shown promise in ameliorating NAFLD symptoms and halting disease progression. However, further investigation is needed to address side effects and personalize therapy approaches. This review summarizes the current understanding of the involvement of NRs in the pathogenesis of NAFLD and explores their therapeutic potential. We discuss the role of several NRs in modulating lipid homeostasis in the liver, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptors (FXRs), REV-ERB, hepatocyte nuclear factor 4α (HNF4α), constitutive androstane receptor (CAR) and pregnane X receptor (PXR).The expanding knowledge of NRs in NAFLD offers new avenues for targeted therapies, necessitating exploration of novel treatment strategies and optimization of existing approaches to combat this increasingly prevalent disease.

Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an increasingly important role in the treatment of hyperlipidemia. In pursuit of potent small molecules that block the PCSK9/low‐density lipoprotein receptor (LDLR) protein−protein interaction (PPI), a series of 2‐phenylquinoline‐4‐carboxylic acid derivatives were designed and synthesized based on previously derived molecules. In the in vitro PPI inhibition test, compounds M1, M12, M14, M18 and M27 exhibited potent activities with IC₅₀ values of 6.25 μM, 0.91 μM, 2.81 μM, 4.26 μM and 0.76 μM, respectively, compared with SBC‐115337 (IC₅₀ value of 9.24 μM). Molecular docking and molecular dynamics simulations revealed the importance of hydrophobic interactions in the binding of inhibitors to the PPI interface of PCSK9. In LDLR expression and LDL uptake assays, the tested compounds M1, M12 and M14 were found to restore LDLR expression levels and to increase the extracellular LDL uptake capacity of HepG2 cells in the presence of exogenous PCSK9. Collectively, novel small‐molecule PCSK9/LDLR PPI inhibitors (especially M12) with in vitro lipid lowering ability, were discovered as lead compounds for further development of hypolipidemic drugs.

Flavonoids are ubiquitous compounds in nature and are found in many Chinese herbal medicines. Due to their biological activity, flavonoids show potential for decreasing insulin resistance (IR), thereby delaying the progression of diabetes and accompanying metabolic syndromes. This review focuses on the mechanisms of flavonoids decreasing IR: (1) the interaction between flavonoids and target proteins of the insulin signalling pathway; (2) bioactivities of flavonoids, such as anti-inflammatory, lipid-lowering and antioxidant. Meanwhile, we summarise the structural characteristics, structure activity relationships and biological activity of flavonoids, providing evidence for their potential in the treatment of IR. Here, we also analyse the potential and limitations of their therapeutic use.

Aging is the subject of many studies, facilitating the discovery of many interventions. Epigenetic influences numerous life processes by regulating gene expression and also plays a crucial role in aging regulation. Increasing data suggests that dietary changes can alter epigenetic marks associated with aging. Caloric restriction (CR)is considered an intervention to regulate aging and prolong life span. At present, CR has made some progress by regulating signaling pathways associated with aging as well as the mechanism of action of intercellular signaling molecules against aging. In this review, we will focus on autophagy and epigenetic modifications to elaborate the molecular mechanisms by which CR delays aging by triggering autophagy, epigenetic modifications, and the interaction between the two in caloric restriction. In order to provide new ideas for the study of the mechanism of aging and delaying aging.