Hepatic ischemia-reperfusion injury (IRI) is a complex pathological process that significantly complicates liver surgery and transplantation, often resulting in irreversible organ damage and adverse clinical outcomes. Characterized by oxidative stress, intracellular calcium overload, inflammatory cascade activation, and endothelial dysfunction, the pathogenesis of hepatic IRI necessitates innovative therapeutic approaches. Advanced drug delivery systems, particularly those utilizing nanomaterials and micromaterials, have emerged as promising solutions due to their enhanced targeting, controlled release, and reduced systemic toxicity. Nanomaterials and micromaterials, in particular, have garnered significant attention due to their unique physicochemical properties and potential for site-specific delivery. This review aims to provide a comprehensive overview of the pathogenesis of hepatic IRI, with a particular focus on the emerging role of advanced drug delivery systems in mitigating injury and improving clinical outcomes. In conclusion, the incorporation of these advanced technologies into the treatment paradigm for hepatic IRI offers substantial potential to augment therapeutic effectiveness and surmount the multifaceted challenges inherent in this condition.

Hepatocellular carcinoma (HCC) is the main histopathological type of liver cancer and the fourth major cause of cancer-related mortality globally, yet the treatment options are very limited. Ferroptosis is a unique iron-dependent form of oxidative cell death process that plays essential regulatory roles in the occurrence and development of HCC. However, the underlying mechanism in ferroptosis regulation in HCC remains inadequately understood. Aberrant activation of fibroblast growth factor 19-fibroblast growth factor receptor 4-βKlotho (FGF19-FGFR4-KLB) signaling is considered carcinogenic driving pathway in patients with HCC. Recently, increasing evidence has shown that FGFR4 inhibition could trigger ferroptosis process in many tumors. However, as an important ligand of FGFR4, the role of FGF19 in the regulation of ferroptosis remains unclear. In this research, results of western blotting and reactive oxygen species (ROS) assay demonstrated that knock down of KLB enhance the expression of TFRC, a driver gene of ferroptosis, thus blocking the ferroptosis inhibitory effect of FGF19. Based on these available evidence and data, we hypothesize that FGF19 signaling inhibit the ferroptotic cell death in HCC cells through FGFR4-KLB co-receptors, while suppression of FGFR4-KLB could block FGF19 signaling, thus trigger ferroptosis process.

Background: In recent years, tissue engineering has experienced rapid development, with bioscaffolds emerging as a focal point of research due to their favorable bioactivity, biocompatibility, and capacity to provide mechanical support for cellular growth. The bioscaffolds have great potential in tissue regeneration. However, conventional natural scaffolds and polymer scaffolds pose risks of immunogenicity, while also face challenges in mimicking the in vivo microenvironment and the biochemical and mechanical properties of natural organs/tissues, which collectively limit their repair capability. The development of decellularized extracellular matrix (dECM) technology offers a viable solution to these challenges, demonstrating considerable potential for advancing organ and tissue regeneration. Technology: This reviews the classification of dECM, outlines various current methods for its preparation, and comprehensively examines its latest advances in tissue repair and regenerative medicine, including applications in skin, bone, nerve, heart, lung, liver, and kidney tissues. Results: This review systematically examines recent advances in dECM production and regenerative medicine applications. We classify dECM subtypes, detail contemporary decellularization protocols, and highlight their biomedical utility. Superior biocompatibility substantially mitigates post-transplant immune rejection risk, underscoring strong clinical translation potential for tissue engineering.

Liver rupture can precipitate catastrophic haemorrhage and life-threatening sequelae, and current surgical interventions are highly invasive. Thus, minimally invasive therapies capable of achieving haemostasis, repairing damaged tissue, and preventing infection are urgently required. Here, we developed an intelligent, biohybrid self-healing hydrogel as a drug delivery system for wound repair and anti-infection. Tannic acid (TA), a natural polyphenolic small molecule with potent antimicrobial and haemostatic properties, was incorporated into the phenylboronic acid-modified hyaluronic acid methacryloyl (HAMA-PBA) self-healing hydrogel as an active component. Poly(N-isopropylacrylamide) (PNIPAM) has, excellent temperature sensitivity, thus, it served as a smart responsive component in the drug-loaded hydrogel. At specific temperatures, PNIPAM’s contraction was triggered to accelerate TA release. The hydrogel exhibited good haemostatic function and effective inhibition of Escherichia coli and Staphylococcus aureus growth. In a rat model of wound healing, the biohybrid hydrogel continuously delivered drugs to inhibit inflammation and accelerate healing. In a liver rupture model, transplantation of the biohybrid hydrogel alleviated sustained liver bleeding and facilitated wound repair. In conclusion, the novel biohybrid hydrogel should support the development of minimally invasive strategies for treating liver injury and preventing infection, providing a promising therapeutic alternative for rehabilitation.

Acute liver failure (ALF) is a fatal syndrome in which necrotic hepatocytes evade immune clearance by upregulating CD47. Although CD47-blocking antibodies show promise, their clinical translation is challenged by systemic toxicity and manufacturing limitations. To address this unmet clinical need, we develop a targeted, cell-free immunotherapy platform based on signal regulatory protein alpha (SIRP alpha)-engineered extracellular vesicles (SIRP alpha-EVs) specifically designed for ALF treatment. Primary human mesenchymal stromal cells (MSCs) are genetically modified to stably overexpress SIRP alpha, enabling the production of clinical-grade, high-purity SIRP alpha-EVs in a 3D microcarrier-based bioreactor. Intravenous injection of SIRP alpha-EVs results in preferential accumulation in CD47-upregulated injured liver tissue, where surface-exposed SIRP alpha antagonizes CD47 signaling and promotes macrophage-mediated clearance of necrotic cells. In the ALF model, SIRP alpha-EVs improve survival rates, reduce liver fibrosis, and promote liver regeneration. This study establishes an engineered EV platform as a scalable, targeted therapeutic strategy for ALF, bridging the gap between mechanism-driven nanomedicine and clinical hepatology.

Sepsis-induced liver injury (SILI) is a severe complication of sepsis and is strongly associated with adverse clinical outcomes. However, the molecular mechanisms driving SILI pathogenesis remain poorly understood. In this study, we applied data-independent acquisition (DIA)-based quantitative proteomics to characterize protein expression profiles in liver tissues from 7 patients with SILI and 14 control patients. A total of 335 proteins were significantly dysregulated in SILI liver tissues, including 126 upregulated and 209 downregulated proteins. GO and KEGG pathway analyses revealed that the upregulated proteins were predominantly enriched in the cellular response to hypoxia and lysosome pathways, whereas the downregulated proteins were mainly associated with metabolic processes, particularly glutathione metabolism. Six key glutathione metabolism-related enzymes (GCLC, GSTO1, SOD1, GPX4, PRDX6, and IDH1) were selected for validation and were confirmed to be markedly reduced in SILI liver tissues by immunoblotting and qPCR. Correlation analyses further demonstrated that decreased expression of these enzymes was strongly associated with elevated markers of inflammation, coagulation disorders, and hepatic dysfunction, linking impaired antioxidant capacity to disease severity. Collectively, our findings reveal a distinct proteomic signature in SILI, characterized by profound suppression of glutathione metabolism, offering mechanistic insight into redox imbalance during SILI. These results highlight glutathione metabolic pathways as promising therapeutic targets for mitigating hepatocellular dysfunction in sepsis.

BACKGROUND:Liver transplantation is a well-established treatment for end-stage liver disease, but the shortage of donor organs and the risk of ischemia-reperfusion injury remain significant challenges. Machine perfusion, an emerging technology, offers a promising solution by dynamically preserving and even repairing donor livers through extracorporeal perfusion. Recent advances in understanding the molecular mechanisms of ischemia-reperfusion injury have further highlighted the potential of machine perfusion to enhance liver preservation and expand the pool of viable donor organs. AIM OF REVIEW:This review aims to comprehensively summarize the research progress on machine perfusion strategies for liver preservation and explore their potential therapeutic applications beyond transplantation. We focus on the classification of machine perfusion methods based on temperature, their integration with novel therapeutic strategies, and their implications for improving liver viability and function. Key Scientific Concepts of Review: The review delves into three main types of machine perfusion: hypothermic machine perfusion (HMP), subnormothermic machine perfusion (SNMP), and normothermic machine perfusion (NMP). Each method offers distinct advantages in preserving liver function and reducing injury. We discuss how machine perfusion can be combined with mesenchymal stem cells, gene regulation, defatting cocktails, and modulators of autophagy and apoptosis to enhance liver repair and regeneration. Additionally, we highlight the potential of machine perfusion in supportive liver treatment, liver cancer therapy, and treatment efficacy evaluation. Despite these advancements, challenges such as optimizing perfusion parameters, understanding the immune status during perfusion, and ensuring long-term functionality of treated livers remain. This review emphasizes the need for further research to address these challenges and facilitate the clinical translation of machine perfusion technologies for advanced liver therapies.

Tissue engineering is considered a promising therapeutic strategy for acute liver failure (ALF), yet it is currently limited by the lack of natural scaffold materials and effective regeneration promoting approaches. Here, we propose a therapeutic strategy using a biohybrid decellularized peritumoral tissue hydrogel loaded with stem cell exosomes (exos) are applied to treat liver failure. Specifically, tissue samples obtained during clinical procedures are typically discarded as medical waste but can serve as natural scaffolds for therapeutic applications. Benefiting from a mild decellularization process, the decellularized peritumoral tissue retains amounts of bioactive substances while maintaining low immunogenicity. Moreover, induced pluripotent stem cell-derived hepatocytes (iPS-Heps) cultured within the decellularized extracellular matrix (dECM) hydrogel exhibit robust metabolic activity. More importantly, the incorporation of mesenchymal stem cells (MSCs) exos enables the effective integration of their inherent regenerative cytokines into the hydrogel. In vitro studies demonstrate that the hydrogel expresses high levels of liver functions, such as albumin (ALB) and the Cytochrome P450 proteins (CYP) family. In a D-galactosamine-induced liver failure rat model, the exos-loaded dECM hydrogel considerably improves survival rates, alleviates liver necrosis, and suppresses local inflammatory responses. This approach not only preserves bioactive substances from the tissue but also enhances metabolic activity in hepatocytes, thereby offering potential for improved clinical outcomes.

Background:Standardized residency training in China requires robust evaluation mechanisms, yet significant disparities exist due to lacking standardized criteria. Current tools like OSCE (simulation-based) and Mini-CEX (workplace-based) have limitations: Mini-CEX excludes surgical skills, while OSCE lacks authentic clinical context. Combining them offers holistic assessment potential but is understudied in hepatobiliary surgery. Methods:A prospective cohort study randomized 36 hepatobiliary surgery residents into: Experimental group (n = 18): Monthly Mini-CEX assessments (evaluating medical interviewing, physical exam, clinical judgment, communication, treatment planning, patient-centered care, and overall competence via 9-point scale) followed by final OSCE. Control group (n = 18): Monthly traditional written/procedural assessments followed by final OSCE.The OSCE (100-point max) comprised stations for history-taking, physical exam, hepatobiliary procedural skills, case analysis and doctor-patient communication. Intergroup comparisons used Student's t-tests and chi-square tests (SPSS 26.0, p < 0.05 significant). Results:Baseline characteristics showed no significant differences between groups. The experimental group achieved significantly higher final OSCE total scores (p < 0.05), with notable improvements in physical examination and doctor-patient communication. No significant differences were found in history-taking, hepatobiliary procedural skills, or case analysis. Satisfaction was significantly higher in the experimental group (1/18 vs. 6/18 dissatisfied in controls). Trainees valued Mini-CEX's real-time feedback and competency mapping. Conclusions:Integrating Mini-CEX and OSCE creates an effective dual-modality system for hepatobiliary surgery residents. It significantly enhances overall clinical competency (especially physical exam and communication) and trainee satisfaction compared to traditional methods. This combined approach provide both formative feedback (Mini-CEX) and summative validation (OSCE), establishing a promising specialty-specific framework. Future multi-center studies are recommended.

Cell therapy is a promising strategy for acute liver failure (ALF), while its therapeutic efficacy is often limited by cell loss and poor arrangement. Here, inspired by liver microunits, we propose a novel spatially ordered multicellular lobules for the ALF treatment by using a microfluidic continuous spinning technology. The microfluidics with multiple microchannels was constructed by assembling parallel capillaries. Sodium alginate (Alg) solution encapsulating human umbilical vein endothelial cells (HUVECs), hepatocytes, and mesenchymal stem cells (MSCs) are introduced into the middle channel and the 6 parallel outer channels of the microfluidics, respectively. Simultaneously, Ca2+-loaded solutions are pumped through the innermost and outermost channels, forming a hollow microfiber with hepatocytes and MSCs alternately surrounding the HUVECs. These microfibers could highly resemble the cord-like structure of liver lobules, bringing about outstanding liver-like functions. We have demonstrated that in ALF rats, our biomimetic lobules can effectively suppress excessive inflammatory responses, decrease cell necrosis, and promote regenerative pathways, leading to satisfied therapeutic efficacy. These findings underscore the potential of spatially ordered multicellular microfibers in treating related diseases and improving traditional clinical methods.

Acute severe autoimmune hepatitis (AS-AIH) is characterized by rapid progression and poor prognosis, with a current lack of effective targeted treatments. Stem cell therapy has demonstrated significant therapeutic promise across various autoimmune diseases. However, the intricate pathogenesis of AS-AIH has hindered the widespread utilization of mesenchymal stem cells (MSCs) in this domain. Herein, it is demonstrated that necroptosis, as the primary mode of cell death in AIH, is crucial in causing AS-AIH. Inflammatory macrophages are the primary cell population involved in necroptosis. Inhibition of the specificity protein 1/sphingosine kinase 1/sphingosine-1-phosphate (SP1/SK1/S1P) axis is responsible for this phenomenon, leading to excessive activation of the intrahepatic immune system and aggravating liver damage. Furthermore, the S1P/S1PR2/YAP axis is the key pathway in initiating liver regeneration during AS-AIH. S1P synthesized by hepatocytes is the primary source, and this process is also regulated by the SP1/SK1 axis. MSCs promote S1P synthesis by macrophages through the delivery of SP1, which inhibits necroptosis and synergistically enhances liver regeneration. In addition, MSCs also promote S1P synthesis in hepatocytes through the same mechanism, further aiding liver regeneration. These findings unveil the core pathogenesis of AS-AIH and provide a theoretical foundation for using MSCs as a potential targeted therapeutic modality.

Background Liver injury and the ensuing regenerative processes exert a profound impact on treatment outcomes. Conventional pharmacotherapy, nutritional adjuncts, and invasive interventions, despite their frequent utilization, often prove inefficacious. Chemical reprogramming, which employs small molecules to emulate extrinsic signaling cues, emerges as a promising therapeutic strategy for liver regeneration, analogous to the developmental processes governing cellular fate. However, its application in hepatic repair necessitates systematic integration. Aim of review This review synthesizes the role of chemical reprogramming in liver regeneration research. It first delineates the mechanisms underlying chemical reprogramming, emphasizing the pivotal role of small molecules in facilitating hepatic regeneration through the modulation of specific signaling pathways and epigenetic modifications. Additionally, it details the derivation of hepatocyte-like cells via chemical reprogramming within the realm of tissue engineering. The review further explores the role of chemical reprogramming in promoting in vivo liver repair and regeneration, particularly within the context of combinatorial therapeutic strategies. Key scientific concepts of review Chemical reprogramming induces the reprogramming of non-hepatic cells into hepatocyte-like cells through the precise regulation of cellular signaling pathways and epigenetic modifications by small molecules, thereby achieving cellular composition remodeling in injured livers. Current liver regeneration strategies rely on the modulation of endogenous regenerative capacity and cell-based therapies; thus, elucidating the regenerative and reparative roles of chemical reprogramming in liver injury is imperative. Addressing the inherent challenges of chemical reprogramming in hepatic regeneration is also underscored.

Chemotherapy continues to be the principal systemic treatment modality for neuroblastoma patients, yet the absence of accurate in vitro tumor microenvironment models has significantly limited chemotherapeutic efficacy. In this study, innovative bioresponsive hydrogel microfibers is proposed that replicate the mechanical properties of the extracellular matrix surrounding neuroblastoma cells for assessing tumor drug responses. These microfibers feature an alginate/poly (N-isopropyl acrylamide) shell encapsulating a carboxymethyl cellulose core, fabricated through precision microfluidic technology. Due to the precise manipulation afforded by microfluidics, it is possible to continuously generate fibers that encapsulate cells with uniform dimensions and meticulously defined structures. Additionally, the rapid temperature response characteristics enabled the microfibers to mimic the mechanical properties of the extracellular matrix, thereby regulating the cellular pressure environment and rapidly forming highly active three-dimensional tumor spheroids. Ultimately, this findings demonstrate that neuroblastoma spheroids within the microfibers display varying sensitivities to different chemotherapy drugs under distinct external pressure conditions. In conclusion, this biomimetic microfiber platform provides a reliable foundation for replicating the neuroblastoma microenvironment and facilitating clinically relevant drug efficacy assessments.

Liver regeneration is a sophisticated biological process influenced by a complex microenvironment that becomes profoundly altered in various pathological conditions. Current therapeutic approaches, including liver transplantation and pharmacological interventions, face significant limitations such as donor shortages, high costs, immune rejection, and insufficient functional recovery. Thus, alternative and innovative strategies are urgently needed. Biomimetic microenvironments constructed through tissue engineering have emerged as promising platforms, capable of recapitulating the liver’s natural architecture and supporting hepatic cell functions. This review outlines key pathological features and the biological basis underlying liver regeneration, highlighting cellular plasticity, inflammation, extracellular matrix (ECM) remodeling, and immune interactions. It further discusses advanced biomimetic strategies, including 3D cell cultures, decellularized ECM hydrogels, bioprinting technologies, and dynamic culture systems like hollow fiber, fluidized-bed, and microcarrier bioreactors. These innovations facilitate accurate modeling of hepatic functions, maintain cellular differentiation, and enhance regeneration. Despite significant advancements, challenges remain in optimizing microenvironmental fidelity, ensuring clinical scalability, and translating laboratory breakthroughs into effective therapies.

BACKGROUND:Primary spontaneous pneumothorax is a rare disease commonly found in young adults, with unknown aetiology. We aimed to investigate the susceptibility genes and the downstream signalling involved in the development of primary spontaneous pneumothorax. METHODS:We conducted the first large-scale genome-wide association study (GWAS) composed of 2223 patients and 3838 controls. The functional role of the novel susceptibility loci was investigated by both in vivo and in vitro assays. Gene expression profiling in lung epithelial cell lines was performed, and conditional gene knockout mice were generated. RESULTS:We identified four novel susceptibility loci at 14q32.2 near C14orf177, at 15q26.3 near CHSY1, at 16q23.1 near CFDP1 and at 22q13.1 near CBX7. The fine-mapping of 22q13.1 revealed a functional variant which regulated CBX7 expression by disrupting the binding activity of transcription factor CREB1. Conditional knockout of Cbx7 in mouse lung epithelial cells resulted in lung cyst formation. Meanwhile, downregulation of the CBX7 elevated the expression of MMP9 and MMP16, which are part of extracellular matrix regulators and may lead to lung injury. CONCLUSIONS:Our GWAS discovered four novel susceptibility loci of primary spontaneous pneumothorax and presented a mechanistic basis for the genetic association with primary spontaneous pneumothorax. The novel susceptibility gene CBX7 and downstream MMP signalling give a new clue to the pathogenesis of primary spontaneous pneumothorax.

The emerging messenger RNA (mRNA) nanomedicines have sprung up for disease treatment. Developing targeted mRNA nanomedicines has become a thrilling research hotspot in recent years, as they can be precisely delivered to specific organs or tissues to enhance efficiency and avoid side effects. Herein, we give a comprehensive review on the latest research progress of mRNA nanomedicines with targeting functions. mRNA and its carriers are first described in detail. Then, mechanisms of passive targeting, endogenous targeting, and active targeting are outlined, with a focus on various biological barriers that mRNA may encounter during in vivo delivery. Next, emphasis is placed on summarizing mRNA-based organ-targeting strategies. Lastly, the advantages and challenges of mRNA nanomedicines in clinical translation are mentioned. This review is expected to inspire researchers in this field and drive further development of mRNA targeting technology.

BACKGROUND & AIMS:This study validated the utilization of the Global Leadership Initiative on Malnutrition (GLIM) criteria in patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma (HCC) undergoing systemic treatment. METHODS:This single-center prospective observational study included adult patients with BCLC stage B or C HCC treated between January 2020 and March 2021. Participants were evaluated using Subjective Global Assessment (SGA) and GLIM for malnutrition diagnosis and followed for three years. Overall survival (OS) served as the primary outcome. Survival differences and adverse events between malnourished and well-nourished patients were analyzed. RESULTS:A total of 237 participants were finally included, 149 participants (62.8 %) were defined as malnutrition according to the GLIM criteria. The median OS was 570 days among all participants. The median OS was 450 days in participants defined as malnutrition by GLIM criteria and the median OS was not reached in participants were well-nourished (p < 0.001). GLIM defined malnutrition was significantly associated with higher mortality risk (HR = 3.32, 95 % CI: 2.30-4.79, p < 0.001). Significantly higher incidence of adverse events (73.2 % vs. 56.8 %, p = 0.010), especially more non-impactful adverse events (2.3 % vs. 12.1 %, p = 0.008) and treatment delays (3.4 % vs. 10.7 %, p = 0.045), were observed in malnourished patients. The predominant GLIM combination was weight loss, low muscle mass and inflammation (18.1 %, 27/149). CONCLUSIONS:GLIM-defined malnutrition aligns well with SGA and is independently associated with shorter OS and more adverse events during systemic treatment in advanced HCC patients.

Hydrogels have emerged as dependable candidates for tissue repair because of their exceptional biocompatibility and tunable mechanical properties. However, conventional hydrogels are vulnerable to damage owing to mechanical stress and environmental factors that compromise their structural integrity and reduce their lifespan. In contrast, self-healing hydrogels with their inherent ability to restore structure and function autonomously offer prolonged efficacy and enhanced appeal. These hydrogels can be engineered into innovative forms including stimulus-responsive, self-degradable, injectable, and drug-loaded variants, thereby enhancing their applicability in wound healing, drug delivery, and tissue engineering. This review summarizes the categories and mechanisms of self-healing hydrogels, along with their biomedical applications, including tissue repair, drug delivery, and biosensing. Tissue repair includes wound healing, bone-related repair, nerve repair, and cardiac repair. Additionally, we explored the challenges that self-healing hydrogels continue to face in tissue repair and presented a forward-looking perspective on their development. Consequently, it is anticipated that self-healing hydrogels will be progressively designed and developed for applications that extend beyond tissue repair to a broader range of biomedical applications.

Acute liver failure (ALF) is a life-threatening illness. The extracorporeal cell-based bioartificial liver (BAL) system could bridge liver transplantation and facilitate liver regeneration for ALF patients by providing metabolic detoxification and synthetic functions. Previous BAL systems, based on hepatoma cells and non-human hepatocytes, achieved limited clinical advances, largely due to poor hepatic functions, cumbersome preparation or safety concerns of these cells. We previously generated human functional hepatocytes by lineage conversion (hiHeps). Here, by improving functional maturity of hiHeps and producing hiHeps at clinical scales (3 billion cells), we developed a hiHep-based BAL system (hiHep-BAL). In a porcine ALF model, hiHep-BAL treatment restored liver functions, corrected blood levels of ammonia and bilirubin, and prolonged survival. Importantly, human albumin and α-1-antitrypsin were detectable in hiHep-BAL-treated ALF pigs. Moreover, hiHep-BAL treatment led to attenuated liver damage, resolved inflammation and enhanced liver regeneration. Our findings indicate a promising clinical application of the hiHep-BAL system.