Xiqiao Zhou

Background: Metabolic dysfunction associated fatty liver disease (MAFLD) is linked to chronic low‐grade inflammation, but the diagnostic value of blood cell–derived inflammatory indices remains unclear. This study assessed their associations and predictive ability for MAFLD and liver fibrosis in a nationally representative population. Methods: This cross‐sectional study included 3501 participants from NHANES 2017–2020. Multivariable logistic regression was used to evaluate associations between six inflammatory indices (AISI, NLR, LMR, PLR, SII and SIRI) and MAFLD with or without liver fibrosis. Restricted cubic spline analysis assessed dose–response relationships, while receiver operating characteristic (ROC) curves and random forest analysis evaluated diagnostic performance and variable importance. Results: Multivariable logistic regression analysis showed that higher values of ln (AISI) and ln (SIRI) were significantly associated with increased odds of MAFLD, whereas ln (SII), ln (LMR) and ln (NLR) were not significantly associated with MAFLD ( p > 0.05). In contrast, ln (PLR) was inversely associated with MAFLD. Among participants with liver fibrosis (LF), higher values of ln (AISI), ln (NLR) and ln (SIRI) were positively associated with MAFLD, whereas ln (PLR) remained inversely associated. No significant associations were observed for ln (LMR) or ln (SII) with MAFLD in the presence of LF. Among the evaluated inflammatory indices, AISI demonstrated the highest discriminatory performance for MAFLD (AUC = 0.752), whereas PLR showed the best performance for predicting liver fibrosis. These findings were further supported by machine learning analysis. Conclusion: Inflammatory indices showed distinct associations with MAFLD and liver fibrosis. AISI was most strongly associated with MAFLD, whereas PLR showed the best performance for fibrosis assessment.

Metabolic dysfunction–associated steatotic liver disease (MASLD) is highly prevalent among patients with cardiovascular disease but remains underrecognized in routine cardiology practice. To address the limited prospective evidence on its progression and clinical impact, we established the CHAIN cohort, a prospective multicenter study enrolling approximately 15 000 adults undergoing coronary evaluation across 40 tertiary hospitals in China. Baseline assessment includes comprehensive cardiometabolic profiling and vibration‐controlled transient elastography for evaluation of liver fibrosis and steatosis. Participants will undergo long‐term follow‐up with repeated liver assessments every 6–12 months. Primary outcomes include liver‐related events and major adverse cardiovascular events, while secondary outcomes include longitudinal changes in liver fibrosis and steatosis and their associations with cardiometabolic risk factors and clinical outcomes. This cohort will provide longitudinal evidence to support risk stratification and integrated heart–liver management in cardiovascular care.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global liver disorder with a rising incidence. Early-to-middle-stage MASLD remains amenable to clinical intervention; without timely management, it may progress to fibrosis and cirrhosis. Therefore, identifying novel targets through integrated multi-technical approaches is critical for preventing and treating MASLD. We developed an integrative multi-omics and spatial proteomic strategy combined with in vitro validation. CyTOF was applied to high-dimensional immunophenotyping of the MASLD liver microenvironment. Key cell populations were then sorted accordingly for mass spectrometry to uncover their core signaling. Focusing on identified key amino acid metabolic enzymes, we performed IMC for spatial single-cell proteomic profiling to localize metabolic aberrant subsets. Finally, functional phenotypes and mechanisms were validated in cell models. CyTOF revealed significant expansion of myeloid-derived cells. Thus, by targeting myeloid-derived cells, proteomic and phosphoproteomic analyses identified two severely impaired amino acid metabolic pathways: the glycine metabolic pathway regulated by AGXT2 and the proline metabolic pathway regulated by PYCR3. We then focused on AGXT2 and PYCR3 for spatial exploration via IMC and ultimately identified a macrophage subset negative for both AGXT2 and PYCR3. These macrophages were significantly elevated within MASLD and exhibited high spatial colocalization with inflammatory cells and fibrotic cells. Compared with dysregulated M1 subsets (M1-C3), dysregulated M2 subsets (M2-C1) indicated stronger pro-inflammatory and pro-fibrotic potential. In vitro models using human and murine cells confirmed that AGXT2⁻PYCR3⁻ macrophages exhibited enhanced proliferation and migration, secreted higher levels of inflammatory cytokines, chemokines, and classic fibrotic proteins, and exerted strong inductive effects on hepatic fibrotic cells, with downregulation of intercellular GSH. Mechanistically, the NF-κB and MAPK/AP-1 pathways were involved in inflammatory responses, while the p-SMAD3(T8)/TGFβ pathway contributed to the fibrotic phenotype. However, the abnormal biological functions could be effectively rescued by supplementation with corresponding amino acids, accompanied by the reversal of aberrant signaling pathway activation. In summary, our study explores an initial link between amino acid metabolism and early-to-middle-stage MASLD. AGXT2⁻PYCR3⁻ macrophages are significantly enriched in MASLD with pro-inflammatory and pro-fibrotic potential, and amino acid supplementation can rescue their aberrant phenotypes in vitro, warranting further validation of their treatment potential.

BACKGROUND Lianhe Xiaozhi ointment (LXO), an innovative formulation derived from the classic Huanglian Wendan decoction, has been granted a national invention patent. With increasing years of clinical expertise within the Jiangsu Province Hospital of Chinese Medicine in China, LXO has become increasingly recognized as a potent remedy for metabolic disorders, particularly metabolic dysfunction-associated steatotic liver disease (MASLD). To date, specific bioactive components and underlying mechanisms remain unclear. AIM To determine the bioactive components of LXO and clarify its mechanisms of action relevant to management of MASLD. METHODS We used ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry and network pharmacology approaches to systematically determine the key bioactive components of LXO and elucidate biological pathways modulated in the treatment of MASLD. Critical signaling pathways were also elucidated via hepatic transcriptomic analysis, and an exhaustive and rigorous exploration of the therapeutic efficacy and underlying mechanisms of LXO in MASLD was conducted via a combination of in vivo and in vitro high-fat model experiments. RESULTS Network pharmacology analysis revealed six pivotal bioactive components within LXO that collectively serve as the cornerstone for their efficacy against MASLD. LXO exerts multiple therapeutic effects, including weight gain retardation, amelioration of glucose and lipid metabolism disturbances, liver injury mitigation, hepatic inflammation alleviation, and correction of gut microbiota disorders. Multiple platform analyses, including hepatic transcriptomics, quantitative real-time polymerase chain reaction, and western blotting, confirmed that LXO induces peroxisome proliferator-activated receptor alpha (PPARα) transcriptional activation in the liver. In vitro studies confirmed that a PPARα antagonist markedly diminishes the lipid-lowering capacity of LXO. CONCLUSION Collectively, our findings suggest that LXO exerts therapeutic effects on high-fat diet-induced MASLD at least in part via PPARα pathway activation.

Invasive Gram-positive bacteria secrete hyaluronidase to degrade wound extracellular matrix (ECM), and conventional topical antimicrobials often fail due to drug dilution, even inducing resistance and chronic infections. Current wound dressings only target pathogens but ignore protecting the endogenous hyaluronic acid (HA) network, a key for bacterial resistance and tissue repair, from bacterial hyaluronidase damage. Inspired by the defensive-offensive integration of sea cucumber cuvierian tubules, we engineered a hyaluronidase-triggered "shield-and-sword" hydrogel (APT-HA), with HA as the bacteria-specific trigger, loaded with aloeemodin (AE)-encapsulated PLGA microspheres and photothermal MXene nanosheets. APT-HA sacrifices exogenous HA to protect endogenous HA from degradation according to bacterial load, while hyaluronidase-induced hydrogel breakdown intelligently releases AE. MXene release combined with NIR irradiation boosts antibacterial efficacy and mild thermal stimulation for tissue repair, using bacteria’s virulence factor to eradicate them. In vitro and in vivo experiments confirm APT-HA effectively eliminates Staphylococcus infections and promotes skin/subcutaneous tissue regeneration, providing a novel strategy for intelligent dressings against complex infected wounds.