Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease. Its molecular etiology remains poorly defined, hindering the development of mechanism-based diagnostics and therapies. Therefore, this study aimed to identify key molecular drivers and causal biomarkers of PSC by integrating transcriptomics, machine learning, and genetic causal inference.

We deployed a computational framework combining transcriptomics, network biology, machine learning, and genetic causal inference. Peripheral blood transcriptomes from PSC patients and controls were analyzed to identify disease-associated modules. Candidate genes were refined via protein-protein interaction networks and a multi-algorithm machine learning screen. Causal inference was performed using two-sample Mendelian randomization, integrating plasma protein quantitative trait loci with PSC genome-wide association study summary statistics.

Transcriptomic analysis revealed a PSC-associated module enriched in ribosome biogenesis and protein homeostasis pathways. A machine learning-optimized nine-gene signature (including PTMA, SUMO1, Shwachman-Bodian-Diamond syndrome (SBDS), RPL7, EIF1AX, ANP32A, PCNA, FAM98A, and MPHOSPH6) achieved high diagnostic accuracy (mean AUC = 0.908) and was consistently downregulated in PSC. This signature was linked to a remodeled immune microenvironment characterized by myeloid skewing and specific transcriptional-immune covariation patterns. Mendelian randomization identified SBDS as a putatively causal protective factor, where genetically instrumented higher plasma SBDS protein levels were robustly associated with a lower PSC risk (inverse variance weighted odds ratio = 0.525, 95% CI: 0.356–0.773, P = 0.001). Sensitivity analyses supported the validity of the Mendelian randomization assumptions.

Our study establishes disrupted ribosome homeostasis as a causal pathway in PSC and nominates plasma SBDS as a high-confidence diagnostic biomarker and therapeutic target. The integrative framework provides a generalizable strategy for discovering causal biomarkers in complex diseases.

Ulinastatin, a broad-spectrum serine protease inhibitor widely used in Asia, has attracted increasing interest for its potential role in critical care. This review summarizes current evidence on its efficacy and safety in acute pancreatitis, severe acute pancreatitis, sepsis, acute respiratory distress syndrome, and perioperative management in cardiac surgery with cardiopulmonary bypass. Meta-analyses suggest that ulinastatin may improve outcomes by reducing mortality, shortening intensive care unit and hospital stays, and attenuating inflammatory responses. In severe acute pancreatitis, its use has been associated with reduced mortality and shorter hospitalization. In sepsis and septic shock, ulinastatin appears to lower all-cause mortality, decrease organ dysfunction scores, and reduce inflammatory markers. Evidence in acute respiratory distress syndrome indicates improvements in the oxygenation index and possible mortality reduction. Perioperative administration during cardiac surgery may mitigate postoperative inflammation and shorten the duration of mechanical ventilation. Despite these encouraging findings, most available studies originate from Asia and are limited by small sample sizes, heterogeneous designs, and inconsistent dosing regimens, which restrict generalizability and prevent standardized recommendations. Additionally, although ulinastatin demonstrates a favorable safety profile with a low incidence of adverse drug reactions, long-term and multinational pharmacovigilance data remain limited. Well-designed international, multicenter randomized controlled trials are required to clarify optimal dosing strategies, confirm clinical efficacy across diverse populations, and determine its independent effects compared with combination therapies. Overall, ulinastatin shows promise as a potential adjunctive therapy in critical care through modulation of inflammation and organ protection, but broader global adoption will depend on higher-quality evidence addressing current methodological gaps.

Mitochondrial DNA (mtDNA) variability, especially heteroplasmy, is believed to affect cellular immunobiogenesis, particularly in monocytes in metabolic syndrome (MetS). This study aimed to identify associations of monocytic mtDNA variability with its phenotypic indices, including cytokine secretion and gene expression, and cardiometabolic parameters in patients with MetS.

The cross-sectional study recruited 87 adult participants, including 34 healthy blood donors (Control group), 21 obese patients (Obesity group), and 32 MetS patients (MetS group). Blood biochemistry tests were performed on venous blood samples, and monocytes (CD14+ cells) were isolated. Monocyte mtDNA was analyzed by next-generation sequencing to identify low (5–10%) and intermediate (10–95%) heteroplasmy, and homoplasmy (≥95%). Expression of genes related to mitochondrial biogenesis, mitochondrial uncoupling, oxidative stress system, and NF-κB signaling was assessed by quantitative real-time polymerase chain reaction. Monocytes cultured with and without lipopolysaccharide for 24 h were analyzed by enzyme-linked immunosorbent assay to assess the cytokine secretion stimulation index.

Monocyte mtDNA showed low variability, but alternative homoplasmies were significantly more common. Intermediate and low heteroplasmy from the protein-coding locus correlated with stenosis (r = 0.396; 95% confidence interval (CI) 0.067–0.647) and low-density lipoprotein levels (r = −0.258; 95% CI −0.45 – −0.043). Intermediate heteroplasmy from the rRNA locus correlated with blood insulin levels (r = −0.228; 95% CI −0.424 – −0.019). D-loop low heteroplasmy correlated with fasting blood glucose (r = 0.275; 95% CI 0.062–0.464). Homoplasmies were associated with creatinine, blood urea nitrogen, and alkaline phosphatase. Intermediate heteroplasmy in mtDNA was associated with the monocyte cytokine secretion stimulation index (R2 = 0.156, P = 0.003). However, there was no significant association between mtDNA variability and the expression of the various genes.

Monocyte mtDNA shows relatively low variability. Low and Intermediate heteroplasmy are associated with cardiometabolic parameters, and intermediate heteroplasmy is associated with the monocyte cytokine secretion stimulation index.

The immunosuppressive tumor microenvironment (TME) limits immunotherapy efficacy in intrahepatic cholangiocarcinoma (ICC). Understanding the molecular drivers of this TME is essential for developing new therapies. This study aimed to identify novel oncogenes that modulate the immune landscape of ICC using a multi-omics approach.

We integrated transcriptomic and proteomic data from our ICC cohorts with public datasets (TCGA-CHOL, GSE107943, OEP002768) to identify genes co-upregulated with PD-L1 (CD274). Single-cell RNA sequencing (scRNA-seq) was used to analyze cell-type-specific expression and intercellular communication. Clinical significance was validated through tissue microarrays and multiplex immunofluorescence in an independent ICC cohort.

Multi-omics screening identified TACC3 as a key candidate in ICC. Elevated TACC3 expression in ICC tissues correlated with poor prognosis and promoted tumor cell proliferation and migration. TACC3 activated the STAT3 pathway, increasing PD-L1 transcription. scRNA-seq showed TACC3/PD-L1 interaction in malignant epithelial cells, with PD-L1 co-expressed with FOXP3 in regulatory T cells (Tregs). Cell–cell communication analysis predicted strong interactions between malignant cells and Tregs. TACC3 knockdown reduced PD-L1 expression and inhibited STAT3 and AKT phosphorylation. Clinical validation confirmed co-expression of TACC3, PD-L1, and FOXP3, with high TACC3 levels linked to worse clinicopathological features and shorter progression-free survival.

Our study defines a TACC3-STAT3-PD-L1 axis driving immunosuppression in ICC. TACC3 fosters an immunosuppressive TME by upregulating PD-L1 and is associated with a Treg-rich contexture, suggesting that TACC3 may serve as a potential therapeutic target to overcome ICC immunosuppression.

Lipid metabolism reprogramming drives malignant proliferation and invasiveness in hepatocellular carcinoma (HCC). Beyond supplying energy and membrane components, lipids function as signaling molecules that modulate tumor cell epigenetics and the microenvironment. Accumulating research has clarified the implications of these metabolic alterations in HCC, providing a rationale for targeted therapies. This review summarizes key alterations in lipid metabolism within HCC and explores their mechanistic contributions to tumor progression. It further examines how lipid metabolic shifts in immune and stromal cells of the tumor microenvironment promote HCC advancement. Finally, we discuss the therapeutic potential of targeting lipid metabolism in liver cancer treatment.

Acute leukemias with chimeric fusion genes involving FET (FUS, EWSR1, and TAF15) family proteins and ETS (E26 transformation-specific)-like transcription factors often present with unique clinical and pathological characteristics. This mini-review aims to summarize the clinical and pathological features of acute leukemia cases harboring rearrangements involving the fused in sarcoma (FUS) or Ewing sarcoma breakpoint region 1 (EWSR1) genes.

An extensive literature review was performed on reported acute leukemia cases with fusions involving FUS or EWSR1. The details of the reported cases, as well as summarized information, are presented.

Rare cases of acute leukemia have been found to harbor either FUS or EWSR1 gene rearrangements with ETS or non-ETS proteins as partners and demonstrate heterogeneous clinical and pathological features. Acute leukemias carrying FUS gene rearrangements present with diverse immunophenotypes and are predominantly, but not exclusively, acute myeloid leukemia (AML), with ERG as the most frequent fusion partner. In contrast, acute leukemias with EWSR1 gene rearrangements more commonly present as B-cell acute lymphoblastic leukemia (ALL) and mixed phenotypic acute leukemia (MPAL), with ZNF384 as the predominant partner. At present, FUS::ERG-positive AML is the only specific entity with a FET::ETS fusion that is formally recognized in the World Health Organization 5th edition hematolymphoid tumor classification (WHO-HEM5) and the International Consensus Classification (ICC) systems. Cytogenetic karyotyping and fluorescence in situ hybridization remain crucial tools for detecting chromosomal translocations in over half of acute leukemias harboring FUS or EWSR1 gene rearrangements. However, a subset of patients may exhibit a normal karyotype and require advanced molecular diagnostic methods. EWSR1-rearranged leukemias can be difficult to distinguish from Ewing sarcoma and therefore require particular attention.

As more cases and additional data become available, it may be justified to expand this category of acute leukemias to include other specific acute leukemia entities with fusions involving FET::ETS, such as FUS::FLI1 and FUS::FEV, in addition to FUS::ERG-positive AML. However, additional data are required to support such subclassification. In contrast, AML cases with EWSR1 rearrangements are exceedingly rare and display considerable variability. Cases of B-ALL or B/myeloid MPAL with the EWSR1::ZNF384 fusion may be more appropriately classified together with other ZNF384-rearranged leukemia subtypes. Advanced molecular diagnostic methods, especially RNA-based next-generation sequencing, are suggested to improve the accurate diagnosis of acute leukemias with FUS or EWSR1 fusions. Additional pathologic workup, particularly immunohistochemical staining with hematopoietic markers, is highly recommended to differentiate EWSR1-rearranged leukemia from Ewing sarcoma.

While norepinephrine (NE) is the cornerstone of septic shock resuscitation, “macrocirculation–microcirculation decoupling” at high doses remains a critical clinical challenge. This study aimed to explore the quantitative tipping point where the NE dose shifts from a life-saving vasopressor to a microcirculatory toxin in septic intensive care unit patients.

In this prospective observational study (January–September 2025), we used handheld vital microscopy to monitor sublingual microcirculation (microvascular flow index [MFI], total vessel density, perfused vessel density, proportion of perfused vessels [PPV], and heterogeneity index [HI]) in adult septic patients within 24 hours of admission and on Day 3. Beyond standard linear analysis, generalized additive models were employed to identify the dose–response thresholds associated with microcirculatory deterioration, adjusted for Acute Physiology and Chronic Health Evaluation II, interleukin-6, and systemic hemodynamics.

Of 144 screened patients, 66 were analyzed. The NE dose showed strong linear correlations with lactate (r = 0.583, P < 0.001) and HI (r = 0.444, P < 0.001), and negative correlations with MFI (r = −0.492, P < 0.001). Crucially, generalized additive models analysis revealed a significant nonlinear “cliff effect”: when the NE dose exceeds the 0.71–0.80 µg/kg/min threshold (PPV: 0.71 µg/kg/min, HI: 0.72 µg/kg/min, MFI: 0.80 µg/kg/min), microcirculatory perfusion parameters deteriorate abruptly (all P < 0.05). Multivariable Cox regression identified an NE dose of 0.80 µg/kg/min as an independent predictor of increased mortality (hazard ratio = 1.32, 95% confidence interval: 1.28–3.10, P = 0.039).

In patients with septic shock, higher NE doses were associated with impaired microcirculatory perfusion and worse outcomes. These findings support individualized vasopressor titration and suggest that microcirculatory monitoring may help identify patients at risk of vasopressor-associated microvascular dysfunction.