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Hepatic ischemia/reperfusion injury (IRI) is an unavoidable course in liver transplantation, during which the immune response of inflammation plays a leading part. MicroRNA-450b-5p (miR-450b-5p), which has been reported to participate in several inflammatory diseases, was investigated in this study. The purpose of this study is to identify the potential function of miR-450b-5p toward remission of hepatic IRI and elucidate the specific mechanism. Herein we found that expression of miR-450b-5p, interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6 was stimulated in hepatic IRI. Inhibition of miR-450b-5p could remarkably alleviate mouse hepatic IRI and improve liver function measured by hematoxylin–eosin (HE) staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), and enzyme-linked immunosorbent assay (ELISA). We further assessed protein expression undergoing Western blot and immunofluorescence, and discovered that miR-450b-5p suppressed alpha B-crystallin (CRYAB), thus restraining the inhibitory κB kinase (IKK) β-mediated canonical nuclear factor-κB (NF-κB) signaling, instead of the noncanonical path guided by IKKα in hepatic IRI. In addition, we demonstrated CRYAB as an activator of M2 polarization through protein kinase B (Akt) 1/mammalian target of rapamycin (mTOR), thus resulting in relief of liver IRI. Combination treatment containing both paths revealed a better antidamage efficacy than adjusting either path alone, suggesting that the joint therapy might be a promising solution in hepatic IRI.

Neutrophil extracellular traps (NETs) play important roles in hepatic ischemic reperfusion injury (IRI) and acute rejection (AR)-induced immune responses to inflammation. After liver transplantation, HMGB1, an inflammatory mediator, contributes to the development of AR. Even though studies have found that HMGB1 can promote NET formation, the correlation between NETs and HMGB1 in the development of AR following liver transplantation has not been elucidated. In this study, levels of serum NETs were significantly elevated in patients after liver transplantation. Moreover, we found that circulating levels of NETs were negatively correlated with liver function. In addition, liver transplantation and elevated extracellular HMGB1 promoted NET formation. The HMGB1/TLR-4/MAPK signaling pathway, which is initiated by HMGB1, participates in NET processes. Moreover, in the liver, Kupffer cells were found to be the main cells secreting HMGB1. NETs induced Kupffer cell M1 polarization and decreased the intracellular translocation of HMGB1 by inhibiting DNase-1. Additionally, co-treatment with TAK-242 (a TLR-4 inhibitor) and rapamycin more effectively alleviated the damaging effects of AR following liver transplantation than either drug alone.

With the rising demand for liver transplantation (LT), research on acute rejection (AR) has become increasingly diverse, yet no consensus has been reached. This study presents a bibliometric and latent Dirichlet allocation (LDA) topic modeling analysis of AR research in LT, encompassing 1399 articles. The United States, Zhejiang University, and the University of California, San Francisco emerged as leading contributors, while Levitsky J and Uemoto SJ were key researchers. The most influential journals included the American Journal of Transplantation, Journal of Hepatology, and Transplantation. The analysis reveals a transition from traditional histological assessments to molecular diagnostics, genetic and epigenetic profiling, and noninvasive biomarkers such as donor-derived cell-free DNA (dd-cfDNA) and microRNAs. Advances in immune checkpoint inhibitors (ICIs), cell-based therapies (Tregs, mesenchymal stem cells (MSCs)), AI-guided immunosuppression, and nanoparticle-mediated drug delivery systems reflect a growing emphasis on precision medicine. In addition, recent exploration of microbiome-based therapies and regenerative medicine, including MSCs and their extracellular vesicles, offers promising new avenues for reducing long-term immunosuppressive drug dependency and enhancing graft survival. These developments not only improve early AR detection and personalized treatment but also reduce toxicity, foster immune tolerance, and expand the scope of individualized therapeutic options. Global collaboration, supported by cutting-edge research and AI-driven decision-making, remains essential for refining AR strategies, improving graft survival, and achieving better long-term patient outcomes. Graphical Abstract

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide. Its high incidence and poor prognosis are closely associated with complex molecular mechanisms. Circular RNAs (circRNAs), a class of non-coding RNAs, play significant regulatory roles in tumorigenesis and progression. However, their specific functions and mechanisms in lung cancer remain largely unclear. This study aims to elucidate the expression pattern and molecular mechanisms of circ0515 in lung cancer, particularly its roles in tumor proliferation, migration, and metabolism. The study revealed that circ0515 is significantly upregulated in lung cancer tissues and cell lines, specific knockdown of circ0515 using short hairpin RNA (shRNA) or antisense oligonucleotide (ASO) significantly inhibits lung cancer cell proliferation, migration, and xenograft tumor formation. On one hand, circ0515 acts as a molecular sponge for miRNA-328-3p, upregulating its downstream target gene YWHAZ, thereby activating the AKT signaling pathway and significantly promoting lung cancer cell proliferation and migration. On the other hand, circ0515 recruited RNA binding motif protein 45 (RBM45) to stabilize SDHB mRNA, promoting SDHB expression and mitochondrial oxidative phosphorylation and succinate metabolism, leading to increased cisplatin resistance in lung cancer cells. These findings not only advance our understanding of the functional roles of circ0515 in lung cancer but also provide a theoretical basis for considering circ0515 as a potential therapeutic target for NSCLC.

Acute rejection (AR) is a significant complication in liver transplantation, impacting graft function and patient survival. Kupffer cells (KCs), liver-specific macrophages, can polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes, both of which critically influence AR outcomes. Angiopoietin-like 4 (ANGPTL4), a secretory protein, is recognized for its function in regulating inflammation and macrophage polarization. This study investigates the effects of ANGPTL4 on KC polarization through cellular interactions between hepatocytes (HCs) and KCs. Using a rat orthotopic liver transplantation model, we observed reduced ANGPTL4 expression during AR, whereas increased ANGPTL4 levels were linked to immune tolerance. Administration of ANGPTL4 recombinant protein improved liver function, suppressed inflammation, and promoted M2 polarization of KCs. Co-culture experiments demonstrated that hepatocyte-derived ANGPTL4 significantly modulates KC polarization and inflammatory responses, mainly by inhibiting the NF-κB signaling pathway. The results emphasize the promise of ANGPTL4 as a therapeutic target to reduce AR and improve liver transplant outcomes by influencing hepatocyte-KC interactions.

Although the drug therapeutic targets of acute respiratory distress syndrome (ARDS) are still unclear and no specific drugs for ARDS treatment have been found, some breakthroughs have been gradually made in the biological target pathways such as endothelial injury. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database suggests that Acetyl-11-keto-β-boswellic acid (AKBA), a processed product of boswellic acid, may be an effective intervention for ARDS. After preliminary in vitro and in vivo verification of the protective role of AKBA on ARDS, in order to explore the mechanism of AKBA in ARDS, we used transcriptomic and proteomic methods to explore its main targets, and used molecular docking and cell thermal shift assay (CETSA) to further reveal the potential value of bone marrow stromal cell antigen 2 (BST2) as a target. We subsequently examined the effect of AKBA targeting BST2 on tubule formation, cell proliferation (Colony formation and EdU assay), migration (transwell and scratch assays), apoptosis and autophagy levels both in vitro and in vivo, and protein changes (analyzed by Western blotting analysis). Our results show that the unphosphorylated signal transducers and transcription activation factors (U-STAT1) bins to the BST2 transcription promoter to encourage more AKBA anchoring the human pulmonary microvascular endothelial cells (HPMECs), thus inhibiting apoptosis and autophagy, promoting migration and tube formation, and restraining the cecal ligation and puncture (CLP) induced lung tissue damage in mice. In conclusion, AKBA treatment may be a potential strategy in the intervention of ARDS. Alternatively, BST2 may contribute to the anchoring of AKBA to HPMECs, and STAT1 as a transcription factor promoting BST2 expression may bind to its promoter.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study investigates the role and mechanisms of ADAM9 as a biomarker and potential therapeutic target in HCC. Utilizing RNA-sequencing data and clinicopathological characteristics from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we conducted survival and meta-analyses, functional enrichment, and immune infiltration studies. Additionally, we evaluated the effects of ADAM9 silencing on HCC cell proliferation, migration, and invasion through in vitro experiments. Our results demonstrate that high ADAM9 expression is associated with poor prognosis and increased immune infiltration in HCC patients. Furthermore, ADAM9 knockdown significantly inhibited tumor cell proliferation and migration. These findings indicate that ADAM9 is a promising prognostic biomarker and potential therapeutic target in HCC. In conclusion, ADAM9 could offer avenues for developing strategies to inhibit tumor progression and improve patient outcomes.

Purpose The predictive sensitivity of carbohydrate antigen 19-9 (CA19-9) in assessing the prognosis of intrahepatic cholangiocarcinoma (ICC) remains inadequate. Integrating CA19-9 with tumor volume offers a potentially viable strategy for improving prognostic accuracy. This study aimed to develop a prognostic model utilizing volume-adjusted CA19-9 (VACA) for ICC patients. Patients and Methods A retrospective analysis was conducted on data from 436 ICC patients. These patients from two centers were divided into the training (n = 291, Center 1) and validation (n = 145, Center 2) cohorts. Using the training cohort, univariate and multivariable Cox regression analyses were employed to identify clinicopathological characteristics significantly associated with overall survival (OS) and recurrence-free survival (RFS), which enabled the construction of prognostic nomograms both with and without VACA. The nomograms’ discriminatory and calibration abilities were assessed using receiver operating characteristic (ROC) curves, decision curve analysis (DCA) curves, and calibration curves, applying both training and validation cohorts. Results VACA emerged as an independent variable that significantly correlated with prognosis. The nomogram incorporating VACA demonstrated superior accuracy in predicting OS and RFS rates compared to the model without VACA. In the validation cohort, the nomogram with VACA yielded area under the ROC curve (AUC) values of 0.695 (95% CI = 0.597∼0.793) and 0.666 (95% CI = 0.559∼0.773) (1- year), 0.662 (95% CI = 0.518∼0.806) and 0.651 (95% CI = 0.446∼0.857) (3- years), and 0.701 (95% CI = 0.486∼0.916) and 0.703 (95% CI = 0.428∼0.978) (5- years) for OS and RFS, respectively, along with improved calibration and DCA curves. Conclusions VACA, formed by integrating tumor volume with CA19-9, exhibits promising prognostic capabilities. The nomogram incorporating data from two centers and utilizing VACA demonstrates robust prognostic performance and holds clinical utility. Condensed abstract Combining CA19-9 with tumor volume presents a potentially viable strategy for improving prognostic accuracy. The nomogram incorporating VACA demonstrates robust prognostic performance and holds clinical utility.

Hepatic ischemia‒reperfusion injury (HIRI) represents a frequently occurring pathological condition during liver surgery, yet the mechanisms governing HIRI remain inadequately comprehended. Here, we investigate the role of B-cell translocation gene 2 (Btg2) in HIRI. Btg2 is upregulated following HIRI. A 70% HIRI model using hepatocyte-specific Btg2 transgenic and systemic Btg2 knockout mice reveals that Btg2 deteriorates hepatic inflammation and apoptosis. In primary hepatocytes, Btg2 knockdown reduces hypoxia/reoxygenation (H/R)-induced inflammation and mitochondrial stress. Metabolomics indicates that taurine metabolism is significantly affected in the livers of Btg2 -/- mice. Mechanistically, Btg2 suppresses UFMylation of flavin-containing monooxygenase 1 (Fmo1), a key taurine synthesis enzyme, promoting its K48-linked ubiquitination and degradation. Virus-mediated Fmo1 overexpression inhibits ferroptosis, apoptosis, and HIRI significantly both in vivo and in vitro. Virtual screening of natural compounds indicates that Daturataturin A (DTA) inhibits Btg2, thereby attenuating ferroptosis and HIRI. These results suggest that Btg2 may constitute a promising therapeutic target for HIRI. Btg2 suppresses UFMylation of Fmo1, promoting its k48-linked ubiquitination and degradation, thereby restricting taurine synthesis and exacerbating ferroptosis and apoptosis in hepatic ischemia-reperfusion injury.

Background Hepatic ischemia/reperfusion (I/R) injury is one of the major pathological processes associated with various liver surgeries. However, there is still a lack of strategies to protect against hepatic I/R injury because of the unknown underlying mechanism. The present study aimed to identify a potential strategy and provide a fundamental experimental basis for treating hepatic I/R injury. Method A classic 70% ischemia/reperfusion injury was established. Immunoprecipitation was used to identify direct interactions between proteins. The expression of proteins from different subcellular localizations was detected by Western blotting. Cell translocation was directly observed by immunofluorescence. HE, TUNEL and ELISA were performed for function tests. Result We report that tripartite motif containing 37 (TRIM37) aggravates hepatic I/R injury through the reinforcement of IKK-induced inflammation following dual patterns. Mechanistically, TRIM37 directly interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), inducing K63 ubiquitination and eventually leading to the phosphorylation of IKKβ. TRIM37 enhances the translocation of IKKγ, a regulatory subunit of the IKK complex, from the nucleus to the cytoplasm, thereby stabilizing the cytoplasmic IKK complex and prolonging the duration of inflammation. Inhibition of IKK rescued the function of TRIM37 in vivo and in vitro. Conclusion Collectively, the present study discloses some potential function of TRIM37 in hepatic I/R injury. Targeting TRIM37 might be potential for treatment against hepatic I/R injury.Targeting TRIM37 might be a potential treatment strategy against hepatic I/R injury. Graphical Abstract