Ferroptosis, an iron-dependent form of regulated cell death, serves as an important mechanism associated with cancer progression. Natural compounds, particularly alkaloids, have emerged as attractive candidates for regulating ferroptotic cell death, thereby providing a promising anticancer strategy. However, the molecular mechanisms underlying their antitumor effects remain poorly understood. In this study, we aimed to investigate the antitumor effects and underlying mechanisms of natural alkaloids against hepatocellular carcinoma (HCC).

An alkaloid library was used to screen alkaloids with anti-HCC activity. A combination of proteomic profiling, in vitro functional assays, and in vivo animal experiments was performed to explore the biological roles and molecular mechanisms of the lead compound.

Through high-throughput screening of an alkaloid library, we identified palmatine (PAL), an active component isolated from Fibraurea recisa Pierre, as a potential ferroptosis sensitizer in HCC cells. PAL treatment triggered typical ferroptotic features in HCC cells, including elevated ferrous iron, reactive oxygen species, and lipid peroxidation, along with decreased glutathione levels. Importantly, the pro-ferroptotic effect of PAL was significantly abolished by two ferroptosis inhibitors, ferrostatin-1 and deferoxamine. Mechanistically, PAL directly interacted with troponin T1 (TNNT1) to trigger its K48-linked polyubiquitination and subsequent protein degradation. Ectopic TNNT1 overexpression significantly rescued PAL-mediated ferroptosis and abrogated its tumor-suppressive effects. In vivo animal models further confirmed that PAL suppressed tumor growth by downregulating TNNT1, with a favorable safety profile.

This study reveals a previously unrecognized role of PAL as a ferroptosis sensitizer and highlights its translational potential for anti-HCC therapy.

Biliary atresia (BA) is a severe pediatric cholangiopathy characterized by rapidly progressive liver fibrosis. This study aimed to characterize scar-associated macrophages and investigate the role of plasminogen (PLG)–plasminogen receptor with a C-terminal lysine (PLGRKT) signaling in BA-associated fibrogenesis.

Single-cell RNA sequencing and spatial transcriptomics were applied to liver tissues from patients with BA and non-BA controls. Key findings were validated in an independent cohort using quantitative polymerase chain reaction and multiplex immunohistochemistry. The functional role of the PLGRKT pathway was further examined using primary human peripheral blood mononuclear cell-derived macrophages with small interfering RNA (siRNA)-mediated PLGRKT knockdown, together with co-culture systems involving LX-2 hepatic stellate cells and human liver organoids. In vivo therapeutic potential was evaluated in a murine bile duct ligation model of cholestatic liver fibrosis using macrophage-targeted Plgrkt–Trem2 antibody–siRNA conjugates.

In BA, scar-associated macrophages (SAMs) increased with fibrosis progression and co-localized with hepatic stellate cells in fibrotic areas. PLGRKT was upregulated in BA liver tissue and increased during monocyte-to-macrophage differentiation. In primary human macrophages, PLG induced a PLGRKT-dependent pro-fibrotic phenotype, and conditioned medium from these cells increased COL1A1 deposition in hepatic stellate cells and human liver organoids. In vivo, macrophage-targeted Plgrkt–Trem2 antibody–siRNA conjugates reduced SAM accumulation and attenuated bile duct ligation-induced liver fibrosis.

These findings support a role for SAMs and the PLGRKT–SAM axis in BA-associated liver fibrosis and suggest that PLGRKT warrants further investigation as a potential macrophage-directed anti-fibrotic target.

Biliary duct invasion (BDI) is an underrecognized growth pattern of colorectal cancer (CRC) liver metastases that can mimic intrahepatic cholangiocarcinoma or intraductal papillary neoplasm of the bile duct. Its prevalence and clinicopathologic associations remain unclear. This study aimed to determine the prevalence of BDI and its clinicopathologic associations in surgically resected CRC liver metastases.

We retrospectively analyzed 133 consecutive patients who underwent hepatic resection for CRC liver metastases. Clinicopathologic variables, including age, sex, resection type, tumor differentiation, lymphovascular invasion (LVI), tumor budding, surgical margin status, and primary tumor characteristics, were compared between BDI-positive and BDI-negative cases. Categorical variables were analyzed using the chi-square, Fisher exact, or Fisher-Freeman-Halton exact test, as appropriate; continuous variables were analyzed using the Mann-Whitney U test.

BDI was identified in 19 of 133 cases (14.3%). Male sex showed the strongest numerical trend toward BDI (84.2% vs. 61.4%, P = 0.096), and LVI showed a nonsignificant numerical trend toward higher BDI rates (26.3% vs. 12.3%, P = 0.149). No clinicopathologic variable in the primary cohort analysis reached statistical significance after Bonferroni correction (α = 0.0050).

BDI occurs in approximately 14% of surgically resected CRC liver metastases in this cohort. Male sex and LVI show nonsignificant numerical trends toward higher BDI rates, but these findings should be interpreted cautiously given the limited sample size. Accurate histopathologic recognition of BDI and its distinction from intrahepatic cholangiocarcinoma remain important for correct pathologic diagnosis. Further prospective studies are warranted to clarify the clinicopathologic and prognostic significance of BDI.

Biliary atresia (BA) is the leading cause of pediatric obstructive cholestasis and a major indication for liver transplantation in infants. Organoid models are increasingly used to investigate BA pathogenesis and therapeutic responses, but incomplete methodological and clinical reporting may limit cross-study comparison and translational interpretation. This study aimed to map the landscape of BA-related organoid research, identify major reporting gaps, and propose the Biliary Atresia Minimum Reporting Standard (BA-MRS) as a preliminary framework for improving reporting completeness.

PubMed, Scopus, and Web of Science Core Collection were searched on March 8, 2026, in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) and the 2024 Joanna Briggs Institute (JBI) Manual for Evidence Synthesis. Reporting completeness was assessed using a 36-item BA-MRS across six domains, scored as fully reported, partially reported, not reported, or not applicable.

Twenty-six studies published between 2020 and 2026 were included. Fibrosis and epithelial–mesenchymal transition were the most frequently studied themes, whereas only one study linked organoid findings to post-Kasai outcomes. BA case/model definition, ethics approval, and differentiation protocols were fully reported in all applicable studies (100%). In contrast, contamination monitoring (3.8%), core biliary function assays (34.6%), and clinical outcome linkage (26.3%) were poorly reported. Culture System and Sample Acquisition showed the lowest domain-level fully reported rates (58.1% and 63.2%, respectively).

BA organoid research has progressed beyond early model development, but reporting remains insufficient for robust comparison, reproducibility, and clinically meaningful interpretation. BA-MRS may serve as a preliminary framework for improving standardized reporting in future studies.

Fuzheng Huayu, a patent herbal product, has shown promise in liver fibrosis and cirrhosis. The effect of Fuzheng Huayu on portal hypertension due to cirrhosis and the consequent complications needs further investigation. In this study, we aimed to evaluate the association of adjunctive Fuzheng Huayu plus entecavir with liver-related events and variceal regression in patients with compensated HBV-related cirrhosis.

A post hoc analysis was conducted using data from two randomized controlled trials implemented at eight clinical centers in China (ClinicalTrials.gov numbers: NCT02945982; NCT02945956). Patients with compensated hepatitis B virus-related cirrhosis were enrolled from October 2017 to March 2021. The primary endpoint was a composite of liver events and the individual components, including variceal bleeding, ascites, overt hepatic encephalopathy, and hepatocellular carcinoma.

A total of 218 participants (Fuzheng Huayu group: 110 and control group: 108; mean age, 51.5 years; 66.5% male; median observational follow-up time, 23.1 months) were included in the primary analysis. The occurrence of total liver events was less frequent in the Fuzheng Huayu group than in the control group (hazard ratio = 0.408 [0.187–0.892], P = 0.020). Among the individual components of liver events, the incidence of ascites was significantly lower in the Fuzheng Huayu group than in the control group (1.8% vs. 9.3%, P = 0.016). In addition, the rate of variceal regression was significantly higher in the Fuzheng Huayu group (27.3% vs. 10.2%, P < 0.001). Finally, there were no significant differences in the occurrence of adverse events between the two groups.

In this post hoc analysis of two randomized controlled trials, adjunctive Fuzheng Huayu plus entecavir was associated with fewer liver-related events, particularly ascites, and a higher rate of variceal regression than entecavir alone in patients with compensated hepatitis B virus-related cirrhosis. These findings warrant confirmation in adequately powered prospective studies.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a multifactorial disorder driven by complex interactions among genetic, epigenetic, transcriptional, proteomic, metabolic, and microbiome factors. Single-omics technologies have provided valuable insights into disease mechanisms, yet each layer captures only a partial view of MAFLD pathogenesis. Recent advances in multi-omics integration allow systematic dissection of molecular networks, cell differentiation trajectories, intercellular communication, and spatial organization, revealing causal links between molecular alterations and tissue phenotypes. Horizontal integration connects different omic layers within the same biological state, while longitudinal integration captures dynamic changes across disease stages. Emerging spatial transcriptomics, proteomics, and metabolomics techniques further enable in situ mapping of cellular and molecular heterogeneity, uncovering spatially defined pathogenic niches and regulatory hubs. Collectively, these integrated approaches offer a multidimensional framework for understanding MAFLD progression, identifying potential biomarkers, and guiding precision therapeutic strategies. Future efforts should focus on standardized multi-omics pipelines, interdisciplinary collaboration, and functional validation to translate these insights into clinical applications.

Inter-individual variability in drug efficacy and toxicity remains a major obstacle to precision therapeutics. Candidate-gene pharmacogenomics and star-allele-based guidelines have established clinically useful examples, but they cannot capture the full spectrum of mechanisms that shape drug response. Pharmacogenomic genome-wide association studies (pharmacoGWAS) extend this framework by enabling discovery beyond known pharmacogenes and can identify human genetic variants associated with efficacy, adverse drug reactions, dose requirements, pharmacokinetics, and pharmacodynamics. This mini-review aims to summarize practical principles for human pharmacoGWAS, with emphasis on study design, phenotype and exposure definition, reproducible bioinformatics pipelines, gene-expression-based functional interpretation, and clinical translation. This review discusses randomized trials, prospective cohorts, biobanks, electronic health records, claims databases, and rare adverse-event designs, highlighting the specific biases that arise because drug response is defined among exposed individuals. It then outlines core analytical steps, including genotype quality control, imputation, ancestry-aware association testing, mixed models, survival and longitudinal analyses, rare-variant aggregation, replication, and meta-analysis. Particular attention is given to expression quantitative trait loci, splicing quantitative trait loci, and protein quantitative trait loci, tissue prioritization informed by the Genotype-Tissue Expression project, transcriptome-wide association studies, and colocalization as tools for prioritizing candidate genes and plausible mechanisms. Finally, we propose a translation framework connecting discovery to clinical validity, guideline development, electronic health record decision support, and equitable implementation across diverse populations. When combined with rigorous epidemiology and functional genomics, pharmacoGWAS may help translate genome-wide signals into safer and more effective prescribing.

Bilateral above-knee amputation stump ulcers with poor arterial inflow, multidrug-resistant infection, and bone involvement are rare and difficult to manage. We report a 52-year-old man who developed nonhealing bilateral stump ulcers more than one month after emergency bilateral amputation for extensive aortoiliac and lower-extremity arterial thrombosis. On admission on January 6, 2026, the right stump wound measured approximately 16.0 × 13.0 cm, with exposed femoral bone, purulent medullary drainage, and necrotic tissue; the left measured 18.0 × 12.0 cm, with slough and persistent exudation. Wound culture yielded carbapenem-resistant Klebsiella pneumoniae, and right femoral bone pathology supported chronic necrotizing osteomyelitis. Because immediate revascularization was not feasible, we used a staged debridement strategy—repeated selective debridement preserving viable tissue, with negative pressure wound therapy (NPWT) as a bridge between operations—combined with delayed stump repair, culture-guided antimicrobial therapy, anticoagulation, analgesia, vascular protection, and nutritional support. NPWT was applied in seven cycles over approximately 54 days. The wounds achieved complete closure by discharge on March 16, 2026. At follow-up on March 30, 2026, there was no exudation, sinus tract, recurrent dehiscence, exposed bone, recurrent infection, or significant stump pain, although prosthetic fitting was not yet possible. This case suggests that NPWT combined with serial staged debridement may offer short-term salvage for selected complex infected amputation stumps when arterial inflow is poor and one-stage closure is unsafe; however, durability and generalizability remain uncertain.

The clinical spectrum from cirrhosis to hepatocellular carcinoma (HCC) reflects interactions among hepatic dysfunction, systemic inflammation, and tumor burden. Whether circulating biomarkers add value beyond clinical parameters remains uncertain. This study aimed to evaluate an exploratory Model for End-Stage Liver Disease (MELD)–neutrophil-to-lymphocyte ratio (NLR)-based clinical–inflammatory phenotyping framework for discriminating advanced HCC features and to determine whether circulating hsa_circ_101555 provides incremental discriminatory value beyond this framework.

This single-center cross-sectional study included 92 consecutive patients (30 with cirrhosis without HCC and 62 with HCC). Patients were classified into three exploratory clinical–inflammatory phenotypes using a hierarchical MELD–NLR algorithm (Phenotype I, n = 25; II, n = 33; III, n = 34). Circulating hsa_circ_101555 was quantified by reverse transcription quantitative polymerase chain reaction. Receiver operating characteristic analysis evaluated Barcelona Clinic Liver Cancer stage C among patients with HCC (n = 62; events = 28). Internal validation used bootstrap resampling.

Higher-risk phenotypes included progressively larger proportions of patients with HCC and greater frequencies of advanced tumor characteristics. The combined MELD–NLR model showed the highest discrimination (the area under the receiver operating characteristic curve (AUC) 0.90; 95% confidence interval 0.82–0.97), with 85.7% sensitivity, 82.4% specificity, and 83.9% accuracy. This performance exceeded that of NLR alone (AUC, 0.80) and MELD alone (AUC, 0.77). Circulating hsa_circ_101555 was associated with smaller tumors and an earlier Barcelona Clinic Liver Cancer stage but showed modest discrimination (AUC, 0.69) and did not improve the MELD–NLR model (ΔAUC = 0.002; DeLong P = 0.79).

The exploratory MELD–NLR-based clinical–inflammatory framework identifies patient groups with differing frequencies of advanced HCC features. Circulating hsa_circ_101555 provides no incremental discriminatory value beyond routinely available clinical–inflammatory parameters and requires external validation before clinical use.