BACKGROUND Liver transplantation is the only treatment for acute and chronic liver failure, but the global organ shortage has increased reliance on extended criteria donor livers, which are more susceptible to ischemia-reperfusion injury. While static cold storage is standard, these grafts often require improved preservation strategies. AIM To summarize the current state of small animal liver machine perfusion (MP), highlight variability in protocols, and emphasize the need for standardization to guide future research. METHODS A comprehensive literature search of PubMed was conducted to identify studies on small animal (rat and mouse) ex vivo liver MP. Only English-language animal studies were included, with no restrictions on publication date. Relevant full-text articles were reviewed, and reference lists were screened to ensure completeness. RESULTS Small animal liver MP provides a cost-effective model to explore dynamic preservation strategies. Rat perfusion studies face challenges including dual-vessel perfusion, maintaining physiological perfusate volumes, and lack of standardized protocols. Open- and closed-circuit setups have distinct advantages and limitations, and experimental designs vary widely across studies. CONCLUSION This review illustrates the wide variability in small animal liver MP protocols and underscores the urgent need for standardization. Addressing these inconsistencies will enhance reproducibility, facilitate comparison across studies, and support the development of optimized liver preservation strategies.

Background: Liver cirrhosis is a systemic disease characterized by progressive hepatic dysfunction and frequent decompensation events. Conventional prognostic models such as the Child–Turcotte–Pugh (CTP) and Model for End-stage Liver Disease (MELD) scores primarily reflect liver-specific severity and may not fully capture the multidimensional vulnerability of patients with cirrhosis. Frailty, a syndrome reflecting reduced physiological reserve, has emerged as a potential prognostic marker in this population. Methods: In this prospective single-center cohort study, 134 patients with liver cirrhosis were enrolled between March and October 2021 and followed at three-month intervals. Frailty was assessed at baseline using the Fried Frailty Index (FFI). Patients were categorized as fit/prefrail or frail. The primary endpoints were cirrhosis-related complications, unplanned hospitalizations, and all-cause mortality. Associations between frailty, its individual components, and clinical outcomes were evaluated. Results: Frailty was present in 41% of patients. Frail patients were older and had higher MELD and CTP scores. During follow-up, frailty was significantly associated with higher rates of ascites (p < 0.001), hepatic encephalopathy (p < 0.001), hepatorenal syndrome (p < 0.001), spontaneous bacterial peritonitis (p = 0.01), and unplanned hospitalizations (p < 0.001). Mortality occurred in 22% of frail patients compared with 3.8% in non-frail patients (p < 0.001). Each frailty component, including reduced grip strength, slow gait speed, low physical activity, exhaustion, and unintentional weight loss, was independently associated with adverse outcomes. Conclusions: Frailty, as assessed by the Fried Frailty Index, is a strong predictor of complications, hospitalization, and mortality in patients with liver cirrhosis. Incorporating frailty assessment into routine clinical practice may improve risk stratification and guide long-term management strategies.

Huanggan Decoction (HGD), as a special Chinese medicine preparation, has good effects in clearing heat, removing dampness, eliminating jaundice. HGD has been used in medical institutions for more than 40 years, and shows an outstanding curative effect in jaundice and cholestatic liver diseases (CLD), makes up for the deficiency of the treatment of CLD. However, the underlying mechanisms of HGD for its therapeutic effects are still not well understood. The hepatoprotective properties of HGD were assessed using a cholestatic liver fibrosis (CLF) rat model induced by ANIT. Serum liver function index was analyzed by automatic chemical analyzer. Serum biomarkers of liver fibrosis and inflammatory factors were detected by ELISA kits. Liver pathology and collagen fiber extent were assessed using HE and Masson's stains. Expressions of pro-fibrotic cytokine TGF-β1 and the indicator of HSC activation α-SMA in liver were assayed by immunohistochemistry. The levels of Smad3, phosphorylated Smad3, MMP1 and TIMP1 were assayed by western blotting. HGD dramatically decreased the serum biochemical indexes, down-regulated the serum biomarkers of liver fibrosis and inflammatory cytokines, reduced the collagen deposition, ameliorated pathological damage. At the same time, HGD notably reduced the level of α-SMA. Additionally, HGD increased MMP1 protein level while decreasing TIMP1 protein level and the p-Smad3 to Smad3 ratio. Findings suggest that HGD demonstrated a remarkable liver-protective effect, potentially linked to halting liver fibrosis progression by maintaining the equilibrium between MMP1 and TIMP1, modulating TGF-β1/Smad signal pathway, suppressing HSC activation, and exhibiting anti-inflammatory characteristics.

Gut microbiome-modulating therapies are potential strategies for managing liver cirrhosis (LC), yet head-to-head comparisons to determine the optimal intervention are lacking. This study aimed to evaluate and rank the therapeutic efficacy of these therapies on liver function and disease progression in patients with LC. We searched major databases (PubMed, Web of Science, Embase, Cochrane Library) for randomized controlled trials (RCTs) published from January 1, 2000, to December 30, 2024. Interventions included probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT) versus placebo or standard care. Primary outcomes were hepatic function indicators; secondary outcomes included inflammatory markers. Data were analyzed using random-effects frequentist network meta-analyses. The study was registered on PROSPERO (CRD420251000506). Seventeen studies comprising 1051 individuals were included. Synbiotics demonstrated the most significant efficacy among all interventions, showing superior reduction in blood ammonia levels compared to placebo (Mean Difference (MD): -5.57), probiotics, and prebiotics. Prebiotics showed significant differences in lowering endotoxin levels compared to placebo (MD: -3.29) and probiotics. Furthermore, relative to placebo, prebiotics significantly reduced tumor necrosis factor-alpha (MD: -2.30) and interleukin-6 levels (MD: -4.60). This network meta-analysis advances current knowledge by establishing an evidence-based hierarchy of efficacy. Synbiotics are most effective for reducing blood ammonia, whereas prebiotics demonstrate superior efficacy in lowering endotoxin and inflammatory markers. These results support a personalized therapeutic approach: prioritizing synbiotics for patients with hyperammonemia, and prebiotics for those characterized by systemic inflammation. Future high-quality RCTs are needed to standardize specific strain combinations.

Accessible liquid biopsies, including analyses of genome-wide cell-free DNA (cfDNA) fragmentation, are emerging for early detection of cancer but remain largely unexplored in other diseases. Here, we used whole-genome sequencing to examine cfDNA fragmentomes in 1576 individuals, including those with liver disease or with other morbidities such as vascular, autoimmune, and neurodegenerative conditions. As a prototype for disease-specific cfDNA fragmentomic biomarkers, we developed a machine learning classifier that detected early liver disease, advanced fibrosis, and cirrhosis with high sensitivity in separate discovery (n=423) and validation cohorts (n=221) and had limited cross-reactivity for other diseases. Genome-wide fragmentome and methylome analyses revealed liver-derived and immune-mediated changes in cfDNA in the circulation of individuals affected with liver disease. Fragmentomic changes were also observed across a range of other human morbidities and reflected disease-specific changes in the circulation. A machine learning model using cfDNA fragmentomes predicted overall survival in separate morbidity discovery (n=571) and validation cohorts (n=231). These analyses demonstrate the connection between cfDNA fragmentomes and an individual's physiologic state and provide previously unrecognized possibilities for cfDNA liquid biopsies across human disease.

Biliary tract cancers (BTCs) in East Asia have traditionally been linked to inflammation-related etiologies. However, metabolic risk factors are increasingly contributing to BTC development. Temporal trends in BTC epidemiology remain underexplored in the Korean population. This study aimed to review 13-year trends in BTCs, focusing on metabolic and inflammatory comorbidities, in a southeastern Korean cancer center historically characterized by a high incidence of inflammation-related BTCs. This retrospective observational study analyzed 2,001 patients diagnosed with BTC at a southeastern Korean cancer center between 2009 and 2021. Data on general demographics (age, sex, smoking, alcohol), metabolic factors (hypertension, body mass index (BMI) ≥ 25kg/m2, diabetes mellitus, hyperlipidemia), and inflammatory conditions (viral hepatitis, liver cirrhosis, bile duct stone, liver fluke infection) were collected from electronic medical records. Annual trends in clinical and demographic variables were evaluated using the Cochran-Armitage trend test. The cohort comprised 680 patients with gallbladder cancers and 586 patients with intrahepatic, 367 patients with perihilar, and 368 patients with distal cholangiocarcinomas. Gallbladder cancer was more common in females, whereas intrahepatic and distal cholangiocarcinomas were more prevalent in males. Over 13 years, the prevalence of hypertension and BMI ≥ 25kg/m2 significantly increased (both p < 0.001). The prevalence of diabetes mellitus remained stable at approximately 26%. Although the proportion of patients with inflammatory factors increased from 38.9% to 49.7%, this trend was not statistically significant (p = 0.646). These findings indicate an ongoing epidemiological transition in BTC risk profiles in Korea, with metabolic factors, such as hypertension and obesity, playing an increasingly prominent role.

Liver fibrosis, marked by excessive ECM deposition, can progress to cirrhosis and hepatocellular carcinoma, yet effective treatments are lacking. Since hepatic stellate cell (HSC) activation is central to fibrosis, inhibiting it is a key therapeutic strategy. Vitamin D receptor (VDR) activation can suppress HSC activation by inhibiting the TGFβ/SMAD3 pathway, making it a promising target. However, steroidal VDR agonists' clinical use is limited by hypercalcemia caused by upregulation of calcium metabolism genes. To overcome this, we designed novel steroidal VDR modulators by modifying the side chain to selectively impair transactivation of calcium-related genes while preserving antifibrotic signaling. Among 30 synthesized compounds, D13 exhibited strong VDR affinity and potent antifibrotic activity in vitro. In a bile duct ligation mouse model, D13 significantly alleviated liver fibrosis without inducing hypercalcemia, unlike calcipotriol. Mechanistically, D13 inhibited the TGFβ/SMAD3 pathway without excessively upregulating calcium metabolism genes. Thus, D13 represents a promising antifibrotic candidate warranting further investigation.

Liver fibrosis is a chronic condition that often leads to organ failure. Currently, no effective treatment exists for advanced liver fibrosis. De-repression of the transcription factor Nrf2, by inhibition of the ubiquitin ligase substrate adaptor Keap1, is a promising strategy to treat liver fibrosis because Nrf2 augments cytoprotection and blunts the profibrotic TGF-β pathway. Herein, Nrf2 is reported to control matrix metalloproteinase (MMP) expression during chronic liver injury, and more specifically in macrophages, which play a key role in the resolution of fibrosis. We found impaired expression of Mmp8, Mmp9, Mmp12, and Mmp14 in the livers of Nrf2-knockout (Nrf2-ko) mice compared to wild-type (WT) mice, both basally and following CCl4 damage. Investigation of bone-marrow-derived macrophages (BMDMs) revealed profoundly impaired expression of Mmp8 and Mmp12 in Nrf2-ko BMDMs and a concomitant hyper-expression in Keap1-knockdown (Keap1-kd) BMDMs, which were corroborated by siRNA knockdown of Nrf2 and macrophage-specific conditional knockout of Nrf2. This trend was observed under basal conditions and post-efferocytosis. Total MMP activity was also found to be highest in the conditioned medium of Keap1-kd post-efferocytosis BMDMs. ChIP-seq revealed Nrf2-binding sites upstream of Mmp12, which also showed the strongest expression response to Nrf2. Lastly, through pharmacological de-repression of Nrf2, using TBE-31 to inhibit Keap1, upregulation of MMP expression was observed in BMDMs and livers of mice following acute liver injury. In conclusion, Nrf2 has been shown to be a regulator of MMP expression and activity in stimulated macrophages, which reveals a new mechanism by which Nrf2 regulates macrophage function.

Background. Somatostatin and its synthetic analog octreotide are suppressive hormones that have been used in the treatment of variceal bleeding or bleeding from portal hypertensive gastropathy. They are also used in the treatment of some cancers, including hepatocellular carcinoma (HCC). Experimental evidence reported that they have potentially useful effects on liver inflammation and fibrosis, acting on Kupffer cells (KCs) and hepatic stellate cells (HSCs). However, clinical data is missing. Therefore, the effect of somatostatin and octreotide was studied on several fibrosis mediators in patients with compensated cirrhosis. Patients and Methods. Fifty-eight patients with HCV-related compensated cirrhosis treated with either somatostatin or octreotide for bleeding from portal gastropathy were compared with twenty-nine healthy controls matched for age and sex. Serum levels of three metalloproteases (MMP1, MMP2 and MMP9) and their inhibitors, TIMP1 and TIMP2, were measured. Additional fibrosis and inflammation mediators—such as nitric oxide (NO), TNFα, soluble ICAM-1, and the CC chemokines RANTES (CCL5) and MIP1a (CCL3)—were also measured. Results. Serum levels of MMP1, MMP2, MMP9 and TIMP1 were significantly decreased in cirrhosis (p &lt; 0.01). TIMP2 levels were increased (p &lt; 0.01). RANTES levels were also significantly decreased (p &lt; 0.01), but NO, TNFα, MIP1a and sICAM-1 were significantly increased (p &lt; 0.01). Administration of somatostatin had no effect on MMP2 or MMP9 but significantly decreased all other mediators. Octreotide had similar but milder effects, but it had no effects on MIP1a and sICAM-1 were demonstrated. Conclusions. Somatostatin and octreotide modulate factors implicated in the progression of fibrosis in the short term. Whether they could be used in the long term as treatment for liver diseases with progressive fibrosis or in cases with intense inflammatory reactions, such as alcoholic hepatitis, requires further investigation.

Patient comorbidities and medication intake impact on the mortality rate in revision surgery for periprosthetic joint infection (PJI) of the lower limb. The present study collected data from patients who underwent revision surgery for PJI of total hip arthroplasty (THA) or total knee arthroplasty (TKA). Data regarding comorbidities and medication intake for each patient were collected to investigate whether comorbidities and medication intake influence in-hospital mortality in patients who underwent revision surgery for PJI of a THA or TKA. The present study follows the STROBE Statement. Our institutional databases were searched using the OPS (operation and procedure codes) 5-823 and 5-821 in combination with the ICD (International Statistical Classification of Diseases and Related Health Problems) codes T84.5, T84.7 or T84.8. All patients with hip or knee implant infections who underwent revision surgery were retrospectively retrieved and included in the present study. Data from 346 patients were collected (181 THAs and 165 TKAs). Patients with renal insufficiency demonstrated a statistically significant greater risk of in-hospital mortality (95% CI 0.0131 to 0.1132), as did patients with a history of malignancy (95% CI 0.1478 to 0.7497), and patients with dementia (95% CI 0.0398 to 0.3791). Nicotine and alcohol abuse, diabetes mellitus, arterial hypertension, hereditary thrombophilia, hereditary haemorrhages, cerebrovascular diseases, coronary heart diseases, chronic obstructive pulmonary disease osteoporosis, liver cirrhosis, rheumatoid arthritis, acute dental infection did not influence in the in-hospital mortality rate in patients who underwent revision surgery for PJI of a THA or TKA. Patient medication therapy did not impact the risk of in-hospital mortality in PJI. Patients undergoing revision surgery for PJI after total hip and knee arthroplasty show an increased in-hospital mortality in the presence of the following comorbidities: dementia, renal insufficiency, and history of malignancy. Based on the present results, further infection prevention and geriatric co-management strategies should be evaluated for patients undergoing revision arthroplasty of the hip and knee for PJI.

Resolvin D1 alleviates liver inflammation and fibrosis through SIRT1-mediated NF-κB and TGF-β1/Smads pathways.

Mast cells (MCs) are multifunctional innate immune cells that regulate inflammation, tissue repair, and immune responses, and they are increasingly recognized as contributors to chronic liver disease. In parallel, the aryl hydrocarbon receptor (AhR) has emerged as a key environmental sensor activated by gut-derived tryptophan metabolites such as kynurenine and microbial indoles. The current literature separately describes the role of AhR in MC signaling, as well as the contributions of MCs to liver pathology and the disrupted gut–liver axis, which drives immune dysfunction in chronic liver disease. However, these aspects have been rarely considered together. This review aims to bridge these fragmented areas, providing an integrated framework where AhR-driven MC responses are examined within the gut–liver axis along with their impacts on liver inflammation and fibrosis. We discuss how this microbial–immune dialogue shapes autoimmune and cholestatic liver diseases, including autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cholangitis. Finally, we highlight translational perspectives, from microbiota modulation to AhR-targeting approaches, as potential strategies to control MC-driven hepatic inflammation. By integrating these currently separate concepts, this review offers a novel perspective on the role of MCs as important mediators at the interface of gut-derived signals and liver pathology via AhR signaling, while highlighting innovative therapeutic avenues through the modulation of the microbiota, targeting of AhR, and regulation of MC responses.

To analyse the relationship between central sensitivity to thyroid hormones (THs) and liver fibrosis in a euthyroid population. Central TH sensitivity indices, including the thyroid feedback quantile-based index (TFQI), thyroid stimulating hormone index (TSHI), and thyrotropin thyroxine resistance index (TT4RI), were calculated according to TH levels. Liver stiffness measurement (LSM) values were determined by liver shear wave quantification ultrasonography, and statistical analysis of the above data was conducted. Compared with those in the LSM < 7.3kPa group, the TFQI, TSHI, and TT4RI in the LSM ≥ 7.3kPa group significantly increased (P < 0.001). Trend tests of multiple regression equations indicated that the LSM was positively correlated with the TT4RI (β = 0.413, P < 0.001). In the sex subgroups, the LSM was positively correlated with the TT4RI (β = 0.425, P = 0.03) and TSHI (β = 0.015, P = 0.027) in females; in the age subgroups, the LSM was positively correlated with the TT4RI (inflection point: 8.4kPa, β = 0.324, P = 0.01) and TSHI (inflection point: 8.3kPa, β = 0.01, P = 0.022) before the inflection points in the age < 65 years group; and in the BMI subgroups, the LSM was positively correlated with the TT4RI (inflection point: 5.9kPa, β = 0.437, P = 0.008), TSHI (inflection point: 6.8kPa, β = 0.013, P = 0.008) and TFQI (inflection point: 6.8kPa, β = 0.007, P = 0.045) in the BMI < 30kg/m2 group. Central TH sensitivity decreases as the degree of fibrosis increases in the euthyroid population, particularly among females, individuals aged < 65 years, and those with a BMI < 30kg/m2 within certain ranges.

Near-infrared-II carbon dots offer exceptional deep-tissue penetration for biomedical imaging, but challenges remain in their synthesis and photoluminescence mechanisms. Here, we report three carbon dots (CDs-1, CDs-2, CDs-3) with tunable emission from the visible to the Near-infrared-II (480-1265 nm), synthesized by constructing extended aniline-based frameworks from p-phenylenediamine. Combined structural and density functional theory analyses reveal that the Near-infrared-II redshift arises from the enhanced molecular dipole moments and electron-acceptor ability of the precursor, as well as the accumulation of graphene domains and pyrrolic nitrogen doping during carbonization polymerization, which collectively drive the narrowing of the energy gap. CDs-3 shows 15 mm penetration depth in gallbladder Near-infrared-II imaging (vs. clinically used indocyanine green 2 mm). With 1.44 signal-to-noise ratio and 334.5 μm resolution, it enables precise monitoring of biliary strictures/leakage. Selenium-doping-derived functionalized composite nanomaterials (CDs-3@pPB) exhibit potent reactive oxygen species scavenging and theranostic efficacy in liver fibrosis. This work elucidates the mechanism underlying the redshift of carbon dots emission into the Near-infrared-II and establishes a nanoplatform for hepatobiliary theranostics, demonstrating substantial clinical potential.

Probiotic-derived extracellular vesicles attenuate cholestatic liver damage via gut-liver axis.

Traditional Chinese medicine prescription Mailuoning alleviated liver fibrosis through inhibiting the TGFβ/Smad-mediated extracellular matrix production.

Neuropilin-1 acts as a co-receptor of IL-13 to reprogram macrophages in liver fibrosis.

Liver cirrhosis is accompanied by pathophysiological changes. Due to multiple absorption, distribution, metabolism and excretion (ADME)-related pathophysiological alterations, the estimation of the net pharmacokinetics (PK) change in cirrhotic patients is complex. Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic modeling technique that combines knowledge of physiological and drug-related properties and, thereby, allows the prediction of organism-specific drug PK. For the integration of pathophysiological changes into a PBPK model, such changes need to be quantified appropriately. To date, published liver cirrhosis pathophysiology repositories contain only average changes for three distinct disease stages limiting clinical applicability. Therefore, the aim of this study was the development of a repository that (1) describes physiological alterations throughout the body during cirrhosis progression, (2) quantifies both mean changes and population variability, and (3) adds parameters of not yet included changes. For this purpose, data was gathered and processed using a Markov-Chain-Monte-Carlo (MCMC)-based approach that allowed the handling of heterogenous data and information on population variability. The resulting repository, based on 216,609 data points from 68 literature studies and 208,851 patients from the IBM Explorys electronic health records database, encompasses 30 physiological parameters. Integration into a PBPK modeling framework revealed good predictive performance with 96% of all data points for predicted PK parameter ratios lying within a twofold prediction range. In summary, the presented approach provides an advancement in the field of PK modeling in liver cirrhosis patients, possibly facilitating the planning and analysis of clinical studies in these patients and moving towards virtual studies.

HKDC1 promotes the H3K18 lactylation of the promoter of ORMDL3 to induce the activation of hepatic stellate cells in liver cirrhosis.

FAK-TRIM25 Promotes HSC Activation and Glycolysis by Inhibiting c-Myc Ubiquitination via FBXW7.