Advanced glycation end products (AGEs) are the unwanted by-products of excessive sugar intake, and their generation and accumulation promote aging and disease occurrence. However, the lack of robust biology model and platform for fast evaluating AGE generation and accumulation under intervention of drugs hampers AGEs-targeted therapeutic development. This work described a novel biological high AGEs recombinant extracellular matrix 3D human hepatocellular spheres model was built, under the same cell numbers, this 3D hepatocellular spheres expressed more AGEs over an order of magnitude than monolayer culture cells. Combined with UV curable gelatin methacryloyl (GelMA), biological 3D human hepatocellular sphere were made into a extruded type bio-ink with high AGEs, simply encapsulated in a hepatic lobule shaped micro array polymethyl methacrylate (PMMA) microfluidic chip successfully. Due to this biomimetic fluid microreactor environment, our biological microfluidic chip enables effectively determine the inhibition capacity of compounds on endogenous AGE accumulation with a high sensitivity and in a short time, total determination workflow less than 2.5 h, it takes 1/200 of the time required by mainstream methods. The evaluation results showed that alisol B 23-monoacetate and chlorogenic acid were potential natural AGEs inhibitors. Moreover, the integration of high AGEs bio-ink and microfluidic chip provides a promising tool for AGE-related drug discovery and liver disease research.

The dual barriers formed by the capillarized liver sinusoids and excessive deposited extracellular matrix (ECM) significantly impede the retention of therapeutic agents in the fibrotic liver. Currently, there are limited reports on strategies capable of simultaneously overcoming these barriers. Here, we propose sulfur dioxide (SO2)-releasing nanomotors based on endogenous in vivo reactions to restore the fenestrae of sinusoids and degrade ECM by activating the endogenous signaling pathway to improve the retention of therapeutic agents in the damaged liver. These nanomotors leverage the specific enzyme concentration gradient in damaged liver tissue as a chemoattractant signal, guiding their targeted delivery. The nanomotors incorporate an l-cysteine-based substrate that, upon enzymatic catalysis, generates SO2. The released SO2 can upregulate the cyclic guanosine monophosphate expression to restore the fenestrated phenotype of liver sinusoidal endothelial cells. Concurrently, SO2 can stimulate the endogenous nitric oxide production to induce matrix metalloproteinase-1 activation to facilitate the collagen degradation. The animal experimental model also demonstrates the effective retention of nanomotors in damaged liver tissue and reversal of liver fibrosis.

Increased adipose tissue (AT) dietary fatty acids (DFA) trapping limits fatty acid exposure to lean organs in the face of elevated postprandial nonesterified fatty acid (NEFA) flux from excess AT intracellular lipolysis in prediabetes. We hypothesized that pharmacological inhibition of postprandial AT intracellular lipolysis using short-acting nicotinic acid (NA) would increase AT DFA trapping and limit AT NEFA spillover to lean organs in subjects with prediabetes. Twenty subjects with impaired glucose tolerance and 19 individuals with normal glucose tolerance underwent four postprandial studies with positron emission tomography/computed tomography with radio-labeled fatty acid tracers and stable isotopic palmitate tracers. Over the 6-h postprandial period, NA increased AT DFA partitioning with reciprocal reduction in liver and in muscle. NA also robustly reduced cardiac and liver total (DFA + NEFA) postprandial fatty acid uptake. Short-acting NA administered postprandially thus enhances AT DFA trapping and markedly reduces postprandial hepatic and cardiac fatty acid uptake. (clinicaltrials.gov NCT02808182).

Peroxynitrite (ONOO-) is a highly reactive oxidant formed by the reaction of nitric oxide with superoxide. Excessive ONOO- can be produced by the body in response to multiple diseases, resulting in cell death through oxidation and nitration processes. However, technical challenges arise in detection due to its high reactivity and very short lifespan. In this work, we rationally designed and synthesized a novel tetrazine-hemicyanine-based probe (TZN-HCY). This probe demonstrates the ability to capture ONOO- with high selectivity and sensitivity, enabling the detection and imaging of ONOO- in biological samples with both fluorescence and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The 3,6-disubstituted tetrazine moiety could react with ONOO-, and the hemicyanine skeleton with a permanent positive charge could enhance MALDI MS detection. The responsive performances of the TZN-HCY probe were verified on cell models and livers of hepatic ischemia-reperfusion injury (HIRI) model mice. Due to the applicability to dual-mode imaging, the formation of ONOO- and its content change in the liver of living mice were visualized by fluorescence imaging, while the fine-scale spatial distribution of ONOO- in liver tissues was revealed by MALDI MS imaging. This dual-modal probe could serve as a powerful tool for elucidating the diverse and complex roles of biogenic ONOO- in ischemia-reperfusion injury.

Stem cell functions and ageing are deeply interconnected, continually influencing each other in multiple ways. Stem cells play a vital role in organ maintenance, regeneration, and homeostasis, all of which decline over time due to gradual reduction in their self-renewal, differentiation, and growth factor secretion potential. The functional decline is attributed to damaging extrinsic environmental factors and progressively worsening intrinsic genetic and biochemical processes. These ageing-associated deteriorative changes have been extensively documented, paving the way for the discovery of novel biomarkers of ageing for detection, diagnosis, and treatment of age-related diseases. Age-dependent changes in adult stem cells include numerical decline, loss of heterogeneity, and reduced self-renewal and differentiation, leading to a drastic reduction in regenerative potential and thereby driving the ageing process. Conversely, ageing also adversely alters the stem cell niche, disrupting the molecular pathways underlying stem cell homing, self-renewal, differentiation, and growth factor secretion, all of which are critical for tissue repair and regeneration. A holistic understanding of these molecular mechanisms, through empirical research and clinical trials, is essential for designing targeted therapies to modulate ageing and improve health parameters in older individuals.

Hepatocyte growth factor (HGF)/c-Met signaling critically influences liver fibrosis, but its interaction with neuropilin-1 (NRP-1) in hepatocytes remains unclear. We investigated the role of hepatocyte-specific NRP-1 deletion in liver fibrosis progression and its relationship with the HGF/c-Met pathway.

Hepatocyte-specific NRP-1 knockout mice were generated using the Cre-lox system, and liver fibrosis was induced by carbon tetrachloride injections or a methionine- and choline-deficient diet. Fibrosis severity, hepatocyte injury, and cytokine secretion were evaluated via histology, biochemical assays, and molecular analyses in isolated hepatocytes. In vitro experiments were conducted in primary hepatocytes and Huh7 cells using lentiviral overexpression and knockdown of NRP-1. Chromatin immunoprecipitation and dual-luciferase reporter assays were performed to analyze transcription factor binding to the NRP-1 promoter.

Hepatocyte NRP-1 expression increased significantly during liver fibrosis and was positively correlated with HGF/c-Met expression and fibrosis severity. In vivo, NRP-1 inhibition reduced extracellular matrix accumulation and abnormal angiogenesis in Alb-Cre NRP-1f/f mice. In vitro, NRP-1 blockade inhibited c-Met activation and reduced transforming growth factor-beta and vascular endothelial growth factor secretion in hepatocytes. NRP-1 functioned as a co-receptor for HGF/c-Met, with HGF upregulating NRP-1 expression at transcript and protein levels. NRP-1 promoted fibrosis through the Met/extracellular signal-regulated kinase pathway. Furthermore, HGF increased retinoic acid receptor alpha expression, promoting NRP-1 transcription.

HGF-induced upregulation of hepatocyte NRP-1, mediated by RARA binding to its promoter, drives liver fibrosis through c-Met pathway activation, highlighting NRP-1 as a potential therapeutic target for liver fibrosis.

Liver sinusoidal endothelial cells (LSECs) lose their characteristic fenestrations and become capillarized during the progression of liver fibrosis. Mesenchymal stem cell (MSC) transplantation can reverse this capillarization and reduce fibrosis, but MSC therapy has practical limitations that hinder its clinical use. Here, with the help of artificial intelligence (AI), we show that MSCs secrete a microRNA (miR-325-3p) that helps restore LSEC fenestrations (tiny pores) by modulating their cytoskeleton, effectively reversing capillarization. We further develop a spherical nucleic acid (SNA) nanoparticle carrying miR-325-3p as an alternative to MSC therapy. This SNA specifically enters fibrotic LSECs via the scavenger receptor A (Scara). In three mouse models of liver fibrosis, the SNA treatment restores LSEC fenestrations, reverses capillarization, and significantly reduces fibrosis without adverse effects. Our findings highlight the potential of SNA-based therapy for liver fibrosis, paving the way for targeted nucleic acid treatments directed at LSECs and offering hope for patients.

Liver transplantation is the key treatment for liver failure, yet organ scarcity, exacerbated by high discard rates of steatotic livers, leads to high waitlist mortality. Preclinical models of steatosis are necessary to understand the pathophysiology of the disease and to develop pharmacological interventions to decrease disease burden and liver discard rate. In this paper, we develop an expedited 3D steatotic organoid model containing primary human hepatocytes and non-parenchymal cells. We present our iterative approach as we transition from 2D to 3D models and from immortalized to primary cells to optimize conditions for the development of a 3D human steatosis model. Both primary cell aggregation and steatosis induction time were reduced from the standard, 5-7 days, to 2 days. Our 3D model incorporates human primary hepatocytes from discarded liver tissues, which have not been used in organoids previously due to their rapid loss of phenotype in culture. After optimizing our steatosis induction media there was a mix of macro- and micro-steatosis in these primary hepatocytes which is consistent with the human pathology. Our approach achieves a model reflective of the liver pathology, preserving cellular phenotypes and viability while exhibiting markers of oxidative stress, a key factor contributing to complications in the transplantation of steatotic livers.

This study examines Dabigatran's (Dab) capacity to mitigate methotrexate (MTX)-induced coagulation disorders and endothelial dysfunction, while exploring its effects on oxidative stress and inflammatory pathways (NF-kB/IL-1β/MCP-1, TLR4/NLRP3) in reducing hepatotoxicity. Rats were assigned to four groups: a control group receiving saline intraperitoneally (i.p.); an MTX group with a single MTX dose (20 mg/kg, i.p.) to induce hepatotoxicity; and two pretreatment groups receiving Dab orally at 15 mg/kg and 25 mg/kg for seven days before and 4 days after MTX administration. MTX-treated rats showed significant increases in liver enzymes (ALT, AST, ALP) and reductions in antioxidant enzymes (SOD, GSH), along with elevated coagulation parameters (tissue factor (TF), thrombin, fibrin, plasminogen activator inhibitor-1 (PAI-1)), leading to coagulation disorders. Endothelial dysfunction was evident with reduced eNOS expression, while inflammation increased through elevated iNOS, ICAM-1, and pro-inflammatory cytokines (MPO, NF-kB, TNF-α, IL-1β, MCP-1), alongside activation of the TLR4/NLRP3 inflammasome pathway and decreased IL-10 (p < 0.05). Immunohistochemistry revealed increased cytochrome c and caspase-3 expression, with histopathological damage. Dabigatran mitigated these effects, downregulating liver enzymes, modulating coagulation factors, restoring eNOS levels, and reducing histopathological and inflammatory markers. Dabigatran demonstrates significant therapeutic potential in alleviating methotrexate-induced hepatotoxicity through its antioxidant, anti-inflammatory, anticoagulant, and anti-apoptotic effects. Its regulation of coagulation parameters and endothelial function suggests a protective role against tissue damage, warranting further investigation.

During chronic liver diseases, LSECs undergo a dedifferentiation process contributing to the development of hepatic microvascular dysfunction. Although microRNAs (miRNAs) have been associated with chronic liver disease, their role as modulators of liver endothelial phenotype is mostly unknown. Therefore, the aim of this study was to analyze miRNAs as regulators of hepatic sinusoidal endothelial dysfunction in chronic liver disease to suggest novel and translatable therapeutic options for cirrhosis.

Global expression of miRNAs was determined in primary LSECs from healthy and cirrhotic patients (alcohol abuse) and rats (CCl4 inhalation). LSECs were transfected with the mimetic or inhibitor of dysregulated miRNAs or with quantum dot nano-complexes containing miR-27b-3p or negative control, and endothelial phenotype was analyzed by RNA sequencing, quantitative PCR, and western blot. Endothelial or mesenchymal phenotypes were analyzed in LSEC by RNA sequencing, followed by pathway analyses and gene deconvolution.

In all, 30 and 69 dysregulated miRNAs were identified in human and rat cirrhosis, respectively, of which 6 miRNAs were commonly dysregulated. Specific exogenous downregulation of miR-27b-3p was associated with the upregulation of target genes, suggesting a correlation between loss of miR-27b-3p and LSEC dedifferentiation. Finally, the expression of miR-27b-3p was efficiently and physiologically re-established in cirrhotic LSECs using nano-miR-27b-3p, leading to modulation of 1055 genes compared with the negative control, ultimately leading to inhibition of the endothelial-to-mesenchymal transition process observed in cirrhosis.

Loss of miR-27b-3p expression contributes to LSECs dedifferentiation in cirrhosis. The use of nano-miR-27b-3p represents a new therapeutic option for hepatic diseases coursing with endothelial dysfunction.

Portal hypertension is a driving factor of cirrhosis complications, but the specific molecular mechanism of portal hypertension in cirrhosis remains unclear. The aim of this study was to identify hub genes for predicting persistent progression of portal hypertension in patients with liver cirrhosis.

Related microarray datasets were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis and differential expression genes analysis were used to identify the correlation sets of genes. In addition, protein-protein interaction networks and machine learning algorithms were conducted to screen center of candidate genes. To validate the diagnostic effect of hub genes, receiver operating characteristic curves were utilized in another dataset that is publicly accessible. Furthermore, the CIBERSORT algorithm was employed to investigate the immune infiltration levels of 22 immune cells and their connection to hub gene markers. Immunohistochemistry and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were conducted to validate novel hub genes in clinical specimens.

We obtained 671 differentially expressed genes and 11 module genes related to cirrhotic portal hypertension. Two candidate genes namely oncoprotein-induced transcript 3 protein (OIT3) and lysyl oxidase like protein 1 (LOXL1) were identified as biomarkers. RT-qPCR and immunohistochemistry (IHC) verified the expression of LOXL1 and OIT3 at mRNA and protein levels in liver tissue.

OIT3 and LOXL1 were identified as potential novel targets for the diagnosis and treatment of cirrhotic portal hypertension (CPH).

The incidence of nonalcoholic steatohepatitis (NASH) is increasing annually, posing a significant threat to human health. NASH is typified by hepatic steatosis, inflammation, and hepatocellular injury, frequently culminating in fibrosis and cirrhosis. Yet, the precise pathogenesis of NASH remains to be fully elucidated. The hepatic sinusoid, which serves as the fundamental structural and functional unit of the liver, is intricately composed of endothelial cells, Kupffer cells, and hepatic stellate cells. Consequently, the homeostasis of the hepatic sinusoidal microenvironment may exert a pivotal influence on the progression and prognosis of NASH. However, the limitations of current NASH animal models have significantly impeded advancements in understanding the disease's pathogenesis and the development of effective therapeutic interventions. In light of these challenges, this review endeavors to delve deeper into the critical role of hepatic sinusoidal microenvironment homeostasis in the pathogenesis of NASH, critically analyze the commonly employed animal models, and comprehensively summarize the most recent and promising developments in drug research and development. It is anticipated that these efforts will collectively expedite the advancement of the field of NASH research and therapeutic innovation.

Background: Acute liver failure (ALF) represents a critical medical condition marked by the abrupt onset of hepatocyte damage, commonly induced by etiological factors such as hepatic ischemia/reperfusion injury (HIRI) and drug-induced hepatotoxicity. Across various types of liver injury, oxidative stress, heightened inflammatory responses, and dysregulated hepatic retinol metabolism are pivotal contributors, particularly in the context of excessive reactive oxygen species (ROS). Methods: C-dots were combined with Cu5.4O USNPs to synthesize a cost-effective nanozyme, Cu5.4O@CNDs, which mimics the activity of cascade enzymes. The in vitro evaluation demonstrated the ROS scavenging and anti-inflammatory capacity of Cu5.4O@CNDs. The therapeutic potential of Cu5.4O@CNDs was evaluated in vivo using mouse models of hepatic ischemia/reperfusion injury and LPS/D-GalN induced hepatitis, with transcriptome analysis conducted to clarify the mechanism underlying hepatoprotection. Results: The Cu5.4O@CNDs demonstrated superoxide dismutase (SOD) and catalase (CAT) enzyme activities, as well as hydroxyl radical (·OH) scavenging capabilities, effectively mitigating ROS in vitro. Furthermore, the Cu5.4O@CNDs exhibited remarkable targeting efficacy towards inflammation cells induced by H2O2 and hepatic tissues in murine models of hepatitis, alongside exhibiting favorable biocompatibility in both in vitro and in vivo settings. Moreover, it has been demonstrated that Cu5.4O@CNDs effectively scavenged ROS, thereby enhancing cell survival in vitro. Additionally, Cu5.4O@CNDs exhibited significant therapeutic efficacy in mice models of HIRI and lipopolysaccharide-induced acute lung injury (LPS-ALI). This efficacy was achieved through the modulation of the ROS response and hepatic inflammatory network, as well as the amelioration of disruptions in hepatic retinol metabolism. Conclusions: In summary, this study demonstrates that Cu5.4O@CNDs exhibit significant potential for the treatment of various acute liver injury conditions, suggesting their promise as an intervention strategy for clinical application.

Orchestrated hormonal interactions in response to feeding and fasting play a pivotal role in regulating glucose homeostasis. Here, we show that in obesity, the production of follistatin-like 3 (FSTL3), an endogenous inhibitor of Activin B, in adipose tissue is increased in both mice and humans. The knockdown of FSTL3 improves insulin sensitivity and glucose tolerance in diabetic obese db/db mice. Notably, the overexpression of Activin B, a member of the TGFβ superfamily that is induced in liver sinusoidal endothelial cells by fasting, exerts multiple metabolically beneficial effects, including improvement of insulin sensitivity, suppression of hepatic glucose production, and enhancement of glucose-stimulated insulin secretion, all of which are attenuated by the overexpression of FSTL3. Activin B increases insulin sensitivity and reduces fat by inducing fibroblast growth factor 21 (FGF21) while suppressing glucagon action in the liver by increasing phosphodiesterase 4 B (PDE4B), leading to hepatic glucagon resistance and resultant hyperglucagonemia. Activin B-induced hyperglucagonemia enhances glucose-stimulated insulin secretion by stimulating glucagon-like peptide-1 (GLP-1) receptor in pancreatic β-cells. Thus, enhancing the action of Activin B which improves multiple components of the pathogenesis of diabetes may be a promising strategy for diabetes treatment.

Drug-induced liver injury (DILI) involves multifaceted pathogenesis, necessitating effective therapeutic strategies. Wnt2, secreted by liver sinusoidal endothelial cell (LSEC), activates the Wnt/β-catenin signaling pathway to promote hepatocyte proliferation after injury. To address the dual challenges of targeted delivery and phagocytosis evasion, we develop a combined "eat me/don't eat me" strategy. RLTRKRGLK (RLTR) peptide-functionalized exosomes are engineered by inserting DMPE-PEG2000-CRLTRKRGLK into the lipid membrane of exosome derived from bEnd.3 cell. Surface-displayed RLTR mediates exosomal enrichment in LSEC, while CD47 engineering reduces macrophage clearance via "don't eat me" signaling. Then, lentiviral transfection enables stable encapsulation of functional Wnt2 mRNA into ExoCD47 (designated Wnt2@ExoCD47). In both acetaminophen (APAP) and dimethylnitrosamine (DMN)-induced murine liver injury models, RLTR-Wnt2@ExoCD47 demonstrates LSEC-specific targeting and significant hepatoprotection. This engineered exosome platform provides a therapeutic strategy for DILI.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), has become a pressing global health concern. The complexity of MASLD and the lack of universally effective treatments expose the limitations of current interventions, which focus mainly on lifestyle modifications. Here, we explore the multilayered nature of MASLD, emphasizing its pathophysiology in shaping future medical and lifestyle interventions from a personalized medicine perspective, based on individual molecular profiles. Additionally, we address the limitations of current animal models in reflecting human metabolic syndrome and sex-specific differences. We argue that a holistic approach, integrating social determinants of health, patient preferences, and adherence patterns, is essential for advancing MASLD management effectively.

Acetaminophen (APAP) is safe at therapeutic doses; however, when ingested in excess, it accumulates in the liver and leads to severe hepatotoxicity, which in turn may trigger acute liver failure (ALF). This is known as APAP poisoning and is a major type of drug‑related liver injury. In the United States, APAP poisoning accounts for ≥50% of the total number of ALF cases, making it one of the most common triggers of ALF. According to the American Association for the Study of Liver Diseases, the incidence of APAP‑associated hepatotoxicity has increased over the past few decades; however, the mechanism underlying liver injury due to APAP poisoning has remained inconclusive. The present study aims to comprehensively review and summarize the latest research progress on the mechanism of APAP‑induced liver injury, and to provide scientific and effective guidance for the clinical treatment of APAP poisoning through in‑depth analysis of the metabolic pathways, toxicity‑producing mechanisms and possible protective mechanisms of APAP in the liver.

The liver controls blood homeostasis and depends critically on adequate blood supply. While the global regulation of liver blood flow via the hepatic arterial buffer response is well established, the mechanisms governing hepatic sinusoidal hemodynamics remain elusive. We use laser speckle contrast imaging to investigate the hepatic microvascular blood flow in anesthetized rats. Laser speckle contrast imaging offers a spatial resolution of a few micrometers, enabling visualization of individual microvessels, and a temporal resolution sufficient to track flow dynamics. This allowed us to resolve individual sinusoids and venules on the liver surface and to detect a reduction of the blood flow following local Angiotensin II injections. We show that the microvascular blood flow oscillates with frequencies within the range of 0.05-0.4 Hz, which may be linked to rhythmic contraction of upstream blood vessels. Our findings provide insights into vessel-specific liver microcirculation in vivo, offering new opportunities to explore vascular dysfunction mechanisms in metabolic liver diseases.

Developing drugs for the treatment of Metabolic Associated Steatohepatitis (MASH) has always been a significant challenge. Researchers have been dedicated to exploring drugs and therapeutic strategies to alleviate disease progression, but treatments remain limited. This is partly due to the complexity of the pathophysiological processes, and inadequate knowledge of the cellular and molecular mechanisms in MASH. Especially, the liver non-parenchymal cells (NPCs) like Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells which play critical roles in live function, immune responses, fibrosis and disease progression. Deciphering how these cells function in MASH, would help understand the pathophysiological processes and find potential drug targets. In recent years, new technologies have been developed for single-cell transcriptomic sequencing, making cell-specific transcriptome profiling a reality in healthy and diseased livers. In this review, we discussed how the use of single-cell transcriptomic sequencing provided us with an in-depth understanding of the heterogeneous, cellular interactions among non-parenchymal cells and tried to highlight recent discoveries in MASH by this technology. It is hoped that the summarized features and markers of various subclusters in this review could provide a technical reference for further experiments and a theoretical basis for clinical applications.

Aging is a biological process along with systemic and multiple organ dysfunction. It is more and more recognized that aging is a systemic disease instead of a single-organ functional disorder. Systemic aging plays a profound role in multiple diseases including neurodegenerative diseases, cardiovascular diseases, and malignant diseases. Aged organs communicate with other organs and accelerate aging. Skeletal muscle, heart, bone marrow, skin, and liver communicate with each other through organ-organ crosstalk. The crosstalk can be mediated by metabolites including lipids, glucose, short-chain fatty acids (SCFA), inflammatory cytokines, and exosomes. Metabolic disorders including hyperglycemia, hyperinsulinemia, and hypercholesterolemia caused by chronic diseases accelerate hallmarks of aging. Systemic aging leads to the destruction of systemic hemostasis, causes the release of inflammatory cytokines, senescence-associated secretory phenotype (SASP), and the imbalance of microbiota composition. Released inflammatory factors further aggregate senescence, which promotes the aging of multiple solid organs. Targeting senescence or delaying aging is emerging as a critical health strategy for solving age-related diseases, especially in the old population. In the current review, we will delineate the mechanisms of organ crosstalk in systemic aging and age-related diseases to provide therapeutic targets for delaying aging.

Lipid nanoparticles (LNPs) are now highly effective transporters of nucleic acids to the liver. This liver-specificity is largely due to their association with certain serum proteins, most notably apolipoprotein E (ApoE), which directs them to liver cells by binding to the low-density lipoprotein (LDL) receptors on hepatocytes. The liver's distinct anatomy, with its various specialized cell types, also influences how LNPs are taken up from the circulation, cleared, and how effective they are in delivering treatments. In this review, we consider factors that facilitate LNP's effective liver targeting and explore the latest advances in liver-targeted LNP technologies. Understanding how LNPs are targeted to the liver can help for effective design and optimization of nanoparticle-based therapies. Comprehension of the cellular interaction and biodistribution of LNPs not only leads to better treatments for liver diseases but also delivers insight for directing nanoparticles to other tissues, potentially broadening their range of therapeutic applications.

Background: Activated hepatic stellate cells (aHSCs) play a significant role during the onset of hepatic fibrosis, ultimately leading to excessive deposition of extracellular matrix (ECM) and other typical pathological features, and thus have become a popular target for the treatment of hepatic fibrosis. However, current aHSC-centric therapy strategies achieve unsatisfactory results, mainly due to the lack of approved anti-fibrosis drugs and sufficiently efficient aHSC-targeted delivery systems. In this study, our aim was to develop an Imatinib-loaded nanoparticle delivery system based on a chondroitin sulfate derivative to enhance aHSC targeting efficiency, improve the therapeutic effect for hepatic fibrosis, and investigate the underlying mechanism. Methods: The carboxyl group of chondroitin sulfate and the amino group of 1-hexadecylamine were linked by an amide bond in this study to produce the amphiphilic carrier CS-HDA. Then, the Imatinib-loaded nanoparticles (IM-CS NPs) were designed to efficiently target aHSCs through CD44-mediated endocytosis and effectively inhibit HSC overactivation via PDGF and TGF-β signaling pathways. Results: Both in vitro cellular uptake experiments and in vivo distribution experiments demonstrated that CS-HDA-modified nanoparticles (IM-CS NPs) exhibited a better targeting ability for aHSCs, which were subsequently utilized to treat carbon tetrachloride-induced hepatic fibrosis mouse models. Finally, significant fibrosis resolution was observed in the carbon tetrachloride-induced hepatic fibrosis mouse models after tail vein injection of the IM-CS NPs, along with their outstanding biocompatibility and biological safety. Conclusions: IM-loaded NPs based on an amphiphilic CS derivative have remarkable antifibrotic effects, providing a promising avenue for the clinical treatment of advanced hepatic fibrosis.

Chronic liver disease is a cluster of disorders associated with complex haemodynamic alterations, which is characterised by structural and functional disruptions of the intrahepatic and extrahepatic vasculature. 'Vasomics' is an emerging omics discipline that comprehensively analyses and models the vascular system by integrating pathophysiology of disease, biomechanics, medical imaging, computational science and artificial intelligence. Vasomics is further typified by its multidimensional, multiscale and high-throughput nature, which depends on the rapid and robust extraction of well-defined vascular phenotypes with clear clinical and/or biological interpretability. By leveraging multimodality medical imaging techniques, vascular functional assessments, pathological image evaluation, and related computational methods, integrated vasomics provides a deeper understanding of the associations between the vascular system and disease. This in turn reveals the crucial role of the vascular system in disease occurrence, progression and treatment responses, thereby supporting precision medicine approaches. Pathological vascular features have already demonstrated their key role in different clinical scenarios. Despite this, vasomics is yet to be widely recognised. Therefore, we furnished a comprehensive definition of vasomics providing a classification of existing hepatic vascular phenotypes into the following categories: anatomical, biomechanical, biochemical, pathophysiological and composite.

Sepsis-associated liver injury (SALI) is a common complication in sepsis patients, significantly affecting their prognosis. Previous studies have shown that aspirin can improve the prognosis of septic patients. However, there is currently a lack of clinical evidence supporting the use of aspirin in the treatment of SALI. Therefore, we conducted this study to explore the association between the use of aspirin and the prognosis of patients with SALI.

The patients in this study were obtained from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, version 3.0. The primary outcome was 30-day all-cause mortality. Baseline characteristics between the aspirin and non-aspirin groups were balanced using propensity score matching (PSM). The Kaplan-Meier survival curve and Cox regression analysis were used to investigate the association between aspirin use and the prognosis of patients with SALI.

Of 657 SALI patients in this study, 447 (68%) patients had not used aspirin during hospitalization, whereas 210 (32%) had. After PSM, the 30-day mortality was 33.1% in the non-aspirin group and 21% in the aspirin group, indicating a significantly reduced mortality risk in the aspirin group (HR, 0.57; 95% CI, 0.37-0.90; P = 0.016). Similarly, the results of the multivariable Cox regression analysis and inverse probability weighting (IPW) analysis showed that, compared to the non-aspirin group, the aspirin group had a significantly lower 30-day mortality risk (Multivariable Cox regression analysis: HR, 0.69; 95% CI, 0.48-0.99; P = 0.047; IPW: HR, 0.62; 95% CI, 0.43-0.89; P = 0.010).

Aspirin can reduce 30-day mortality in SALI patients, regardless of the dose or timing of administration. However, careful assessment based on individual differences is essential to ensure the safety and effectiveness of aspirin use.

Accumulating evidence indicates that patients with liver diseases exhibit distinct microbiological profiles, which can be attributed to the bidirectional relationship of the gut-liver axis. Porto-sinusoidal vascular disease (PSVD) has recently been introduced to describe a group of vascular diseases of the liver, involving the portal venules and sinusoids. Although the pathophysiology of PSVD is not yet fully understood, several predisposing conditions, including immunodeficiency, inflammatory bowel disease, abdominal bacterial infections are associated with the increasing in intestinal permeability and microbial translocation, supporting the role of altered gut microbiota and gut-derived endotoxins in PSVD etiopathogenesis. Recent studies have proposed that the gut microbiome may play a crucial role in the pathophysiology of intrahepatic vascular lesions, potentially influencing the onset and progression of PSVD in this context. This review aims to summarize the current understanding of the gut microbiome's potential role in the pathogenesis of hepatic microvascular abnormalities and thrombosis, and to briefly describe their interactions with PSVD. The insights into gut microbiota and their potential influence on the onset and progression of PSVD may pave the way for new diagnostic, prognostic, and therapeutic strategies.

Liver sinusoidal endothelial inflammation/dysfunction and fibrosis are a crucial part of Metabolic Dysfunction Associated Steatohepatitis (MASH) development. TRC105 and M1043 are anti-endoglin (ENG) monoclonal antibodies that bind ENG. In this study, we hypothesized that treatment with anti-ENG antibodies would prevent the progression of LSECs inflammation and fibrosis in vivo and in vitro. MASH was induced in male C57BL/6 mice fed a choline-deficient L-amino acid-defined high-fat diet (CDAA-HFD) for 4 or 8 weeks. In the rescue study, mice were divided into three groups: a control group (chow diet), a MASH group (CDAA-HFD + IgG), and a rescue group (CDAA-HFD + M1043). Later, two groups received rat IgG1 (10 mg/kg) and M1043 (10 mg/kg). In in vitro experiments, inflammation was induced in human LSECs by ox-LDL (50 μg/mL) and treated with TRC105 (300 μg/mL). Liver sinusoidal endothelial inflammation/dysfunction in MASH animals was characterized by endothelial overexpression of ENG, VCAM-1, and ICAM-1 and reduced VE-cadherin and p-eNOS/eNOS expression. M1043 treatment prevented the overexpression of ENG, VCAM-1, and ICAM-1, the progression of liver fibrosis, and the increase of liver-to-body weight ratio. In vitro experiments with TRC105 confirmed the prevention of LSECs inflammation development by reduced ENG and VCAM-1 expression, as well as decreased THP-1 monocytic cell adhesion in ox-LDL activated LSECs. In conclusion, we demonstrate that anti-ENG antibody treatment can prevent LSECs inflammation and fibrosis progression in a MASH animal model and LSECs inflammation in vitro. Thus, we propose directly targeted ENG may represent a promising pharmacological approach for addressing LSECs inflammation and liver fibrosis.

Remote ischemic conditioning (RIC), including pre-conditioning (RIPC, before the ischemic event), per-conditioning (RIPerC, during the ischemic event), and post-conditioning (RIPostC, after the ischemic event), protects the liver in animal hepatic ischemia-reperfusion injuries models. However, several questions regarding the optimal timing of intervention and administration protocols remain unanswered. Therefore, the preclinical evidence on RIC in the HIRI models was systematically reviewed and meta-analyzed in the present review to provide constructive and helpful information for future works. In the present review, 39 articles were identified by searching the PubMed, OVID, Web of Science and Embase databases spanned from database inception to July 2024. According to the preferred reporting items for systematic reviews and meta-analyses guidelines, data were extracted independently by two researchers. The primary outcomes evaluated in this study were those directly related to liver injury, such as alanine transaminase (ALT), aspartate transaminase (AST) and liver histopathology. The risk of bias was assessed using the risk of bias tool of the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE). The findings were expressed as standardized mean difference (SMD) and analyzed using random-effects models. Egger's test was used to evaluate the publication bias. RIC significantly reduced the changes in ALT, AST and liver histopathology (all P<0.00001). These effects had two peaks, with the first peak of RIPerC/RIPostC occurring earlier, regardless of models and species. RIPerC/RIPostC exerted significant effects on changes in ALT and AST [ALT SMD (95% confidence interval (CI]): RIPC -1.97 (-2.40, -1.55) vs. -2.78 (-3.77, -1.78); P=0.142; AST SMD (95%CI): RIPC -1.45 (-1.90, -0.99) vs. -2.13 (-2.91, -1.34); P=0.142], and RIPC had a greater effect on liver histopathology change [SMD (95%CI): RIPC -2.68 (-3.67, -1.69) vs. -1.58 (-2.24, -0.92); P=0.070]; however, no interactions were observed between the two groups in the meta-regression analysis. RIC is the most effective in experimental HIRI, using a 10-25-min dose. These outcomes suggest that RIC may be a promising strategy for treating HIRI; however, future studies using repeated doses in animal models with comorbidities will present novel ideas for its therapeutic application. The protocol of present study was registered with PROSPERO (CRD42023482725).

Hepatocellular carcinoma (HCC) represents a global health challenge, and ranks among one of the most prevalent and deadliest cancers worldwide. Therapeutic advances have expanded the treatment armamentarium for patients with advanced HCC, but obstacles remain. Precision oncology, which aims to match specific therapies to patients who have tumours with particular features, holds great promise. However, its implementation has been hindered by the existence of numerous 'HCC influencers' that contribute to the high inter-patient heterogeneity. HCC influencers include tumour-related characteristics, such as genetic alterations, immune infiltration, stromal composition and aetiology, and patient-specific factors, such as sex, age, germline variants and the microbiome. This Review delves into the intricate world of HCC, describing the most innovative model systems that can be harnessed to identify precision and/or personalized therapies. We provide examples of how different models have been used to nominate candidate biomarkers, their limitations and strategies to optimize such models. We also highlight the importance of reproducing distinct HCC influencers in a flexible and modular way, with the aim of dissecting their relative contribution to therapy response. Next-generation HCC models will pave the way for faster discovery of precision therapies for patients with advanced HCC.

Fat accumulation is the hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD). Given the intimidating nature of its treatment, curcumin (CUR) emerges as a potential therapeutic agent due to its proven effectiveness in managing MASLD. This review aimed to evaluate previous reports on the hepatoprotective and fat-accumulation-reductive effects of CUR administration in preventing or treating MASLD. CUR administration can modulate serum liver enzymes and lipid profiles. The fat accumulation of MASLD is the primary cause of oxidative stress and inflammation. By reducing fat accumulation, CUR may attenuate the inflammation and oxidative stress in MASLD. In addition, CUR has been proven to restore the dysfunctional cellular energy metabolism capacity and attenuate fibrogenesis (antifibrotic agent). Their hepatoprotective effects are associated with fat accumulation in MASLD. Lipid metabolism (lipogenesis, lipolysis, and lipophagy) is correlated with their hepatoprotective effects. CUR has prophylactic and therapeutic effects, particularly in early-stage MASLD, primarily when it is used as a fat reducer. It can be considered an excellent natural therapeutic drug for MASLD because it protects the liver and attenuates fat accumulation, especially in the early stage of MASLD development.

Sepsis is a severe, often life-threatening form of organ dysfunction that arises from an inappropriately regulated host response to infectious pathogen exposure. As the largest gland in the body, the liver serves as a regulatory hub for metabolic, immune, and detoxification activity. It is also an early sepsis target organ such that hepatic dysfunction is observed in 34-46% of patients with sepsis. The precise mechanisms that give rise to sepsis-induced liver injury, however, remain incompletely understood. Based on the research conducted to date, dysregulated systemic inflammation, microbial translocation, microcirculatory abnormalities, cell death, metabolic dysfunction, and liver inflammation may all contribute to the liver damage that can arise in the context of septicemia. This review was developed to provide an overview summarizing the potential mechanisms underlying sepsis-induced liver injury, informing the selection of potential targets for therapeutic intervention and providing a framework for the alleviation of patient symptoms and the improvement of prognostic outcomes.

Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.

Liver sinusoidal endothelial cells (LSECs), with their unique morphology and function, have garnered increasing attention in chronic liver disease research. This review summarizes the critical roles of LSECs under physiological conditions and in two representative chronic liver diseases: metabolic dysfunction-associated steatotic liver disease (MASLD) and liver cancer. Under physiological conditions, LSECs act as selective barriers, regulating substance exchange and hepatic blood flow. Interestingly, LSECs exhibit contrasting roles at different stages of disease progression: in the early stages, they actively resist disease advancement and help restore sinusoidal homeostasis; whereas in later stages, they contribute to disease worsening. During this transition, LSECs undergo capillarization, lose their characteristic markers, and become dysfunctional. As the disease progresses, LSECs closely interact with hepatocytes, hepatic stellate cells, various immune cells, and tumor cells, driving processes such as steatosis, inflammation, fibrosis, angiogenesis, and carcinogenesis. Consequently, targeting LSECs represents a promising therapeutic strategy for chronic liver diseases. Relevant therapeutic targets and potential drugs are summarized in this review.

Therapy failure in patients with metastatic colorectal cancer (mCRC, ∼80% occur in the liver) remains an overarching challenge. Preclinical studies demonstrated that human epidermal growth factor receptor 3 (HER3) promotes colorectal cancer (CRC) cell survival, but therapies blocking the neuregulin-induced canonical HER3 signaling have made little impact in the clinic. Recent studies suggest that the liver microenvironment promotes CRC growth by activating HER3 in a neuregulin-independent fashion, thus elucidation of these mechanisms may reveal new strategies for treating patients with mCRC.

Patient-derived primary liver endothelial cells (ECs) were used to interrogate EC-CRC crosstalk. We conducted proteomic analysis to identify EC-secreted factor(s) that triggers noncanonical HER3 activation in CRC and determined the subsequent effects on mCRC using diverse murine mCRC models. In vitro studies with genetic and pharmacological interventions were used to map the noncanonical HER3 pathway.

We demonstrated that EC-secreted leucine-rich alpha-2-glycoprotein 1 (LRG1) directly binds and activates HER3 and promotes CRC growth distinct from neuregulin, the canonical HER3 ligand. Blocking host-derived LRG1 by gene knockout or a neutralizing antibody impaired mCRC outgrowth in the liver and prolonged mouse survival. We identified protein synthesis activated by the PI3K-PDK1-RSK-eIF4B axis as the biologically relevant signaling cascade downstream of the LRG1-HER3 interaction, which was not blocked by conventional HER3-specific antibodies that failed in prior clinical trials.

LRG1 is a novel HER3 ligand and mediates liver-mCRC crosstalk. The LRG1-HER3 signaling axis is distinct from canonical HER3 signaling and represents a new therapeutic opportunity to treat patients with mCRC, and potentially other types of liver metastases.

The creation of self-organizing liver organoids represents a significant, although modest, step toward addressing the ongoing organ shortage crisis in allogeneic liver transplantation. However, researchers have recognized that achieving a fully functional whole liver remains a distant goal, and the original ambition of organoid-based liver generation has been temporarily put on hold. Instead, liver organoids have revolutionized the field of hepatology, extending their influence into various domains of precision and molecular medicine. These 3D cultures, capable of replicating key features of human liver function and pathology, have opened new avenues for human-relevant disease modeling, CRISPR gene editing, and high-throughput drug screening that animal models cannot accomplish. Moreover, advancements in creating more complex systems have led to the development of multicellular assembloids, dynamic organoid-on-chip systems, and 3D bioprinting technologies. These innovations enable detailed modeling of liver microenvironments and complex tissue interactions. Progress in regenerative medicine and transplantation applications continues to evolve and strives to overcome the obstacles of biocompatibility and tumorigenecity. In this review, we examine the current state of liver organoid research by offering insights into where the field currently stands, and the pivotal developments that are shaping its future.

Sepsis is a life-threatening syndrome characterized by organ dysfunction caused by a dysregulated host response to infection. Sepsis-associated acute liver injury (SA-ALI) is a frequent and serious complication of sepsis that considerably impacts both short-term and long-term survival outcomes. In intensive care units (ICUs), the mortality rate of patients with SA-ALI remains high, mostly due to the absence of effective early diagnostic markers and suitable therapeutic strategies. Recent studies have demonstrated the importance of non-coding RNAs (ncRNAs) in the development and progression of SA-ALI. This review focuses on the critical roles of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in regulating "cytokine storms", oxidative stress, mitochondrial dysfunction, and programmed cell death in SA-ALI, and summarizes the current state and limitations of existing studies on lncRNAs and circRNAs in SA-ALI. By integrating advancements in high-throughput sequencing technologies, this review provides novel insights into the dual potential of ncRNAs as diagnostic biomarkers and therapeutic targets, offers new ideas for SA-ALI diagnosis and treatment research and highlights potential challenges in clinical translation.

Alcoholic hepatitis (AH) and hepatocellular carcinoma (HCC) are common liver diseases. Chronic inflammation caused by AH can progress to alcoholic cirrhosis (AC) and eventually HCC.

This study sought to ascertain potential shared genes between AH and HCC through the utilization of multiple transcriptome databases. Employing an immune infiltration analysis, and calculating the correlation between shared genes and immune infiltration results, in conjunction with independent bulk transcriptome validation sets, led to the identification of core shared genes. Subsequently, single-cell transcriptome data, clinical sample immunohistochemistry experiments, and overexpressed core shared genes in HepG2 cells were employed to validate the core shared genes of AH and HCC.

Through the bulk transcriptome discovery sets of AH and HCC, 206 potential shared genes were identified. After screening with two machine learning algorithms, five shared genes remained. Combining the results of the immune infiltration and bulk transcriptome results from an independent validation cohort, the core shared gene was determined to be RASGRF2. Single-cell data further demonstrated that RASGRF2 and its downstream genes were highly expressed in AH, AC, and HCC tissues. Spatial transcriptome data indicated that RASGRF2 was highly expressed in HCC tumor tissues. Compared with the paracancerous tissues, the RASGRF2 gene was significantly overexpressed in HCC tissues. Overexpression of RASGRF2 in HepG2 cells resulted in significantly enhanced migration, invasion, and proliferation abilities.

RASGRF2 serve as a pathogenic gene that mediates the progression of AH to AC and potentially to HCC.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of liver lesions, ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), that may further progress to cirrhosis. MASLD is estimated to affect more than one third of the general population and it represents a risk factor for end-stage liver failure and liver cancer, substantially contributing to liver-related morbidity and mortality. Although the pathogenesis of MASLD is incompletely understood, it is known to consist of a multifactorial process influenced by extrinsic and intrinsic factors such as metabolic, environmental and demographic features, gut microbiota and genetics. Dysregulation of both extracellular and intracellular lipid composition is known to promote the generation of toxic lipid species, thereby triggering lipotoxicity and cellular stress. These events ultimately lead to the activation of distinct cell death pathways, resulting in inflammation, fibrogenesis and, eventually, carcinogenesis. In this manuscript, we provide a comprehensive review of the role of lipotoxicity during MASLD pathogenesis, discussing the most relevant lipid species and related molecular mechanisms, summarizing the cell type-specific effects and highlighting the most promising putative therapeutic strategies for modulating lipotoxicity and lipid metabolism in MASLD.

The liver sinusoid, mainly composed of liver sinusoidal endothelial cells, hepatic macrophages and hepatic stellate cells, shapes the hepatic vasculature and is key to maintaining liver homeostasis and function. During chronic liver disease (CLD), the function of sinusoidal cells is impaired, being directly involved in the progression of liver fibrosis, cirrhosis, and main clinical complications including portal hypertension and hepatocellular carcinoma. In addition to their roles in liver diseases pathobiology, sinusoidal cells' paracrine communication or cross-talk is being studied as a mechanism of disease but also as a remarkable target for treatment. The aim of this review is to gather current knowledge of intercellular signalling in the hepatic sinusoid during the progression of liver disease. We summarise studies developed in pre-clinical models of CLD, especially emphasizing those pathways characterized in human-based clinically relevant models. Finally, we describe pharmacological treatments targeting sinusoidal communication as promising options to treat CLD and its clinical complications.