Introduction:Central nervous system (CNS) infiltration is a severe complication of acute myeloid leukemia (AML), often leading to relapse and poor prognosis. The underlying mechanisms remain poorly understood, limiting the development of effective targeted therapies. Conventional chemotherapy agents capable of crossing the blood-brain barrier (BBB) carry significant toxicity and fail to eliminate leukemia stem cells. Methods:Using multiple clinical cohorts, we established prognostic prediction model for AML. Using knockdown and overexpression experiments in a mouse leukemia CNS infiltration model, the role of risk factor gene in CNS infiltration was evaluated, along with the attenuating effect of its downstream proteins drug inhibition on leukemia CNS infiltration. Results:We identify Lactoferrin (LTF) as a risk factor associated with poor AML prognosis using a machine learning-based prognostic model. Through LTF knockdown and overexpression in a mouse leukemia model, we demonstrate its pivotal role in CNS invasion. Mechanistically, neutrophil serine proteases (NSPs) act as downstream effectors of LTF, and pharmacological inhibition with Brensocatib effectively blocks AML cell entry into the brain. Discussion:Our findings establish LTF as a mediator of CNS infiltration in AML and highlight NSP inhibition as a promising therapeutic strategy.

Background & Aims: Cancer-associated fibroblasts (CAFs) drive immunosuppression in hepatocellular carcinoma (HCC). However, their metabolic regulation remains poorly defined. We investigated the role of nicotinamide N-methyltransferase (NNMT) in CAFs. Approach & Results: High NNMT expression in CAF tissues was confirmed by western blotting and immunofluorescence staining. Primary CAFs from HCC patients, single-cell RNA-seq (GSE149614), patient-derived organoids (PDOs), and fibroblast-specific NNMT-knockout mice were integrated by metabolomic analyses. NNMT in CAFs binds EZH2 and impedes its nuclear translocation, thereby reducing H3K27me3 enrichment at the promoter of angiopoietin-like 4 (ANGPTL4) to increase ANGPTL4 secretion. Secreted ANGPTL4 engages GLUT1 in HCC cells, activating aerobic glycolysis and increasing histone H3K18la levels. This epigenetic reprogramming transcriptionally upregulates PD-L1 expression, thereby facilitating tumor immune evasion. Additionally, CAF-derived ANGPTL4 promotes angiogenesis in HCC. Therapeutically, targeting the NNMT-ANGPTL4 axis restored CD8+ T-cell activity and synergized with anti-PD-L1 therapy in both patient-derived xenografts (PDXs) and fibroblast-specific NNMT-knockout murine models. Conclusion: We identified an NNMT-ANGPTL4-driven metabolic-epigenetic cascade in CAFs that induces PD-L1-mediated immune evasion, providing a therapeutic strategy to overcome resistance to immunotherapy in patients with HCC.

BACKGROUND & AIMS:Intrahepatic cholangiocarcinoma (iCCA) remains a lethal malignancy with a lack of effective therapies, underscoring the critical need to identify novel therapeutic targets. The high-mobility group protein A2 (HMGA2) is an oncogenic architectural transcription factor aberrantly overexpressed in multiple cancers; yet its function and regulatory mechanisms in iCCA are poorly defined. This study aimed to elucidate the clinical significance and molecular mechanism of HMGA2 in iCCA progression. METHODS:We integrated analyses across 4 independent iCCA cohorts (The Cancer Genome Atlas, 2 Zhongshan Hospital cohorts, and our 192-patient institutional cohort). Functional investigations were conducted using iCCA cell lines and multiple mouse models, including xenograft, syngeneic, YAP/AKT-driven spontaneous iCCA, and metastasis models. RESULTS:We demonstrated that HMGA2 was significantly upregulated in iCCA, correlating with poor survival, and exhibited sexually dimorphic prognostic effects with a female-specific link to perineural invasion. Functionally, HMGA2 depletion suppressed iCCA cell proliferation, migration, in vivo tumor growth and metastasis. Mechanistically, HMGA2 expression was positively regulated by the N6-methyladenosine reader insulin-like growth factor 2 messenger RNA-binding protein 1 (IGF2BP1), which directly bound to and stabilized HMGA2 messenger RNA via its KH3-4 domains in an N6-methyladenosine-dependent manner. High IGF2BP1 expression predicted poor iCCA prognosis, was required for HMGA2-driven progression, and the axis promoted PI3K-AKT pathway activation. CONCLUSIONS:Our results reveal a critical role for the IGF2BP1-HMGA2 axis in iCCA pathogenesis, thereby highlighting its potential as a therapeutic target.

Specific Na+ imaging within cancer cells is of great significance for understanding their physiological state and malignant progression. Despite great success, Na+ imaging methods often face challenges related to specificity and sensitivity. Herein, we designed a fat mass and obesity-associated protein (FTO)-activated DNA walker for the specific imaging of metal ions in cancer cells. Abnormal FTO expression in cancer cells provides high specificity, while the self-amplification mechanism of the DNA walker provides high sensitivity.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis, primarily owing to its capacity of metastasis, underscoring the urgent need to identify novel drivers of HCC progression. While neurotransmitter receptors are increasingly recognized as regulators of tumor biology, the role of the gamma-aminobutyric acid type A receptor delta subunit (GABRD) in HCC remains unexplored. Here, we show that GABRD is significantly upregulated in HCC tissues and cell lines, and high expression of GABRD correlates with poor prognosis in HCC patients. Loss- and gain-of-function studies demonstrated that GABRD promotes HCC cell proliferation, invasion, and migration in vitro, and accelerates tumor growth in both subcutaneous xenograft and spontaneous HCC models in vivo. Mechanistically, we find that GABRD physically interacts with the interleukin-10 receptor alpha subunit (IL-10RA). This interaction orchestrates the activation of the JAK2-STAT3 signaling axis, driving epithelial-mesenchymal transition (EMT). Inhibition of JAK2-STAT3 and IL-10RA partially reverses the tumorigenic effects of GABRD. Our study establishes the GABRD-IL-10RA-JAK2-STAT3 axis as a critical oncogenic driver in HCC and identifies GABRD as a promising therapeutic target for improving HCC outcomes.

The absence of effective early diagnostic biomarkers for hepatocellular carcinoma (HCC) is the main reason for its poor prognosis. To address this problem, we investigated and identified differentially expressed genes in HCC by integrating publicly available database resources with the transcriptomic sequencing data obtained by our research group. We initially identified 42 genes that were consistently upregulated in advanced-stage HCC, giant HCC, and multifocal HCC. Among these genes, POLD1 (DNA polymerase delta 1 catalytic subunit) was considerably upregulated across all HCC subtypes analyzed, showing consistent overexpression compared to our RNA sequencing data. However, the role of POLD1 in HCC remains poorly understood, as does its expression pattern and functional relevance in other types of cancer. Using a panel of bioinformatics tools, we analyzed the expression and prognostic significance of POLD1 across multiple cancer tissues. We found that POLD1 is highly expressed in various malignancies and is associated with poor clinical outcomes, particularly liver cancer, where its expression is significantly negatively correlated with the survival of patients. These findings suggest a role for POLD1 in the progression of HCC. We validated the association between aberrant expression of POLD1 and adverse prognostic outcomes in cancer patients. Our results revealed that POLD1 plays an important role in the development of HCC and highlighted its potential as a novel diagnostic and therapeutic target in progressive HCC, offering valuable information that can be used to develop precision medicine strategies in oncology.

Most of the lung's gas-exchange surface forms during alveologenesis and its disruption causes bronchopulmonary dysplasia (BPD) in infants, characterized by alveolar simplification and myofibroblast accumulation. BPD also increases the risk of adult emphysema, marked by alveolar loss. Despite this connection, mechanisms linking these conditions and effective treatments are still lacking. We identify hedgehog-interacting protein (HHIP), associated with both BPD and emphysema, as a critical regulator of alveologenesis. During this process, Hhip-expressing cells expanded, accompanied by hedgehog (Hh) signaling inhibition and myofibroblast transition. Stromal-specific Hhip deletion led to hyperactivation of Hh-IGF1 signaling axis, causing persistent SMA+ myofibroblasts and epithelial stem/progenitor cell senescence. Hyperactivation of this pathway was also observed in human BPD and hyperoxia-induced BPD models. Early Hhip deficiency resulted in adult emphysema with myofibroblast accumulation. We developed a therapeutic Fc-fused HHIP protein that mitigated BPD in neonatal mice and prevented adult emphysema. These findings establish HHIP as a critical regulator of alveologenesis and a therapeutic target for BPD and emphysema.

In the pursuit of green and sustainable development, there is an urgent demand for environmentally friendly adhesives that maintain a stable adhesion under harsh conditions. In this work, bioinspired by the synergistic mechanisms of mussel proteins, we designed a readily accessible and environmentally friendly catechol-functionalized cross-linking adhesive (MPCs) via molecular engineering and thiol-ene click chemistry. By optimizing solvent selection, we preserved a higher density of phenolic hydroxyl groups, significantly enhancing the interfacial adhesion. The resulting adhesive reaches remarkable lap shear strengths of 2.13 MPa in 63 °C water and 1.75 MPa in liquid nitrogen (-196 °C), surpassing most reported catechol-based adhesives. Notably, MPCs exhibit excellent recyclability through thermal reprocessing, retaining strong adhesion even after 10 reuse cycles. Mechanical testing reveals a tensile strength of up to 48 MPa, while the inherent π-π interactions between benzene rings confer photoluminescence under UV irradiation. This property enables fluorescence-based damage detection, as localized mechanical damage causes measurable intensity shifts. Furthermore, MPCs could degrade controllably through ester-linkage hydrolysis in the cross-linker, generating products with excellent biocompatibility. This work not only advances the design of bioinspired adhesives but also provides a sustainable solution for marine-environment and extreme-environment applications.

Severe respiratory viral infections lead to extensive damage to the alveolar epithelium and also induce a robust immune response. How the immune microenvironment interacts with lung stem/progenitor cells and impacts alveolar regeneration is poorly understood. Here, we found that dysplastic KRT5+ basal-like cells, which emerge after severe viral infections, contribute to the recruitment and sequestration of CD4+ effector and CD8+ T cells in the lung after viral clearance in a CXCR3- and integrin α4β7-dependent manner. Persistent CD4+ effector and CD8+ T cells impair alveolar regeneration mediated via airway secretory cells by secreting IFNγ, thereby inhibiting lung functional repair. Importantly, anti-IFNγ treatment improves alveolar regeneration and lung function in vivo. Overall, our study reveals the pathogenetic role of dysplastic KRT5+ cells in alveolar regeneration, serving as a niche for tissue-resident lymphocytes that specifically inhibit alveolar regeneration. Additionally, our findings provide a potential therapeutic strategy to improve alveolar regeneration after viral pneumonia.

BACKGROUND:The high recurrent rate after surgery hinders the survival of patients with hepatocellular carcinoma (HCC). This prospective cohort study aimed to evaluate the efficacy and safety of lenvatinib plus transarterial chemoembolization (TACE) as an adjuvant therapy in HCC patients with high risk of recurrence. METHODS:Patients were enrolled from eight hepatobiliary centers in China. The primary endpoint was disease-free survival (DFS). The secondary endpoints were overall survival (OS) and safety. Additionally, propensity score matching (PSM) and other three propensity score analyses were performed to balance the potential baseline bias to validate the conclusion. The adverse events (AEs) were recorded throughout the study. The study was registered at ClinicalTrials.gov (NCT03838796). RESULTS:A total of 297 patients were enrolled, with 147 in the LEN + TACE group and 150 in the TACE group. Before PSM, the LEN + TACE group achieved significantly better DFS than the TACE group (19.0 vs. 10.0 months, P = 0.011). PSM analysis identified 111 matched pairs. After PSM, the LEN + TACE group also showed better DFS (19.0 vs. 9.0 months, P = 0.018). Other three propensity score analyses yielded similar DFS benefit tendency. Furthermore, favorable OS was also obtained in the LEN + TACE group before PSM. Lenvatinib related AEs of grade 3 or 4 occurred in 28.6 % of the patients in the LEN + TACE group. CONCLUSIONS:Adjuvant lenvatinib plus TACE might be a promising adjuvant approach for HCC patients with high risk of recurrence, which could significantly prolong DFS and potentially OS with a manageable safety profile.

Background:Concurrent chemoradiotherapy (CCRT) is a primary treatment for cervical cancer (CC) and combines chemotherapy and radiation therapy to target cancer cells effectively. However, despite its benefits, it also involves a high risk of recurrence and metastasis, partly due to the resistance of some cancer cells to the treatment. Additionally, CCRT can cause various treatment-related adverse reactions, such as gastrointestinal issues, bone marrow suppression, and skin reactions, which can negatively impact patients' quality of life. Therefore, there is a compelling need to develop more effective treatment strategies that can improve the outcomes of CCRT while minimizing its side effects. This study aimed to investigate the radiosensitizing effects of arsenic trioxide (ATO) on CC and explore its underlying molecular mechanisms. Methods:We conducted both in vitro and in vivo experiments to evaluate the radio-sensitizing properties of ATO. The in vitro effects of ATO were assessed using clonogenic assay, while in vivo effects were evaluated using a xenograft model. Then cell viability, cell cycle, and apoptosis were assessed by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. RNA sequencing was performed to identify the differentially expressed genes. Finally, mRNA and protein expressions of key hub genes were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Western blot, immunofluorescence, and RNA sequencing analyzed molecular mechanisms. Results:ATO significantly enhanced the radiosensitivity of CC cells, as evidenced by reduced colony formation in vitro and inhibited tumor growth in vivo. This enhancement was achieved by impairing the DNA damage repair pathway, specifically through the downregulation of key proteins such as breast cancer 1 (BRCA1) and bloom syndrome protein (BLM). Notably, overexpression of BRCA1 or BLM substantially mitigated ATO's radiosensitizing effects. Conclusions:This study demonstrates that ATO exhibits radiosensitizing effects on CC by inhibiting DNA damage repair. These findings provide theoretical and experimental support for using ATO as a radiosensitizer in CC therapy, potentially leading to improved treatment outcomes, reduced recurrence rates, and enhanced patient survival. Future research should focus on optimizing ATO's dosage and timing as well as evaluating its long-term safety and efficacy in clinical settings.

INTRODUCTION:The clinical benefits of combining immunotherapy with chemotherapy and surgical resection in pancreatic adenocarcinoma remain unclear. The expression and clinical significance of HIF1A in circulating tumor cells (CTCs) in pancreatic adenocarcinoma remains limited. METHODS:This retrospective cohort study compared survival outcomes in pancreatic adenocarcinoma patients treated with two regimens: surgery+chemotherapy (nab-paclitaxel plus gemcitabine)+anti-PD1 (Tislelizumab) (S+AG+anti-PD1) (n = 37), and surgery+chemotherapy (S+AG) (n = 5). The study also evaluated CTCs and HIF1A-positive CTCs as potential prognostic biomarkers. RESULTS:The S+AG+anti-PD1 group (n = 37) showed significantly better progression-free survival (PFS) compared to S+AG (n = 15) in multivariate analysis (HR: 0.426, 95% CI: 0.185-0.983, p = 0.045). Overall survival (OS) differences were not statistically significant between groups. Lower CTC counts (≤1) were associated with longer PFS in surgical patients. This association was confirmed in multivariate analysis, after adjustment for AJCC stages (HR: 0.318, 95% CI: 0.104-0.974, p = 0.045). HIF1A-positive CTCs showed similar trends and prognostic significance to total CTC counts. Advanced AJCC stages remained the strongest independent predictor of worse PFS and OS. CONCLUSION:Combining surgery, chemotherapy, and immunotherapy may improve PFS in resectable pancreatic adenocarcinoma. While CTCs and HIF1A-positive CTCs may have prognostic value, AJCC staging remains the most reliable indicator.

BackgroundLung cancer is a prevalent malignant neoplasm globally and the leading cause of cancer-related mortality, posing a significant threat to human health and imposing a considerable societal burden. Researchers have recently focused more on lipid metabolism in lung cancer. However, to date, there has been no bibliometric analysis of lung cancer in relation to lipid metabolism. This study used bibliometric methods to analyze the link between lipid metabolism and lung cancer.MethodsPublications on lung cancer and lipid metabolism from 1995 to 2024 were sourced from the Web of Science Core Collection (WoSCC). The Microsoft Excel, R-bibliometrix, CiteSpace, and VOSviewer software were used to analyze and visualize the data.ResultsIn this study, a total of 535 publications were identified, with a marked increase in the number of publications observed post-2016. Both China and the United States exerted substantial influence in this domain. Notably, the Chinese Academy of Sciences and Huazhong University of Science and Technology have demonstrated leadership in various aspects of lipid metabolism research related to lung cancer. Professor Ana Ramirez de Molina and Frontiers in Oncology were the most productive authors and journals respectively. Besides, keywords like “lipid metabolism”, “lung cancer”, “expression”, “metabolism” and “growth” were central to current research and are expected to continue driving future trends in lung cancer and metabolism studies.ConclusionsResearch on the relationship between lung cancer and lipid metabolism was still in its early stages. Targeting lipid metabolism in lung cancer represented a promising therapeutic strategy, as inhibiting key enzymes involved in lipid biosynthesis and uptake has the potential to impede cancer progression and mitigate drug resistance. This bibliometric study was the first to thoroughly summarize research trends and developments in this area over the past thirty years, providing scholars with updated insights and identifying future research directions.

BACKGROUND:Arsenic trioxide (ATO) is indicated as a broad-spectrum medicine for a variety of diseases, including cancer and cardiac disease. While the role of ATO in hepatic ischemia/reperfusion injury (HIRI) has not been reported. Thus, the purpose of this study was to identify the effects of ATO on HIRI. METHODS:In the present study, we established a 70% hepatic warm I/R injury and partial hepatectomy (30% resection) animal models in vivo and hepatocytes anoxia/reoxygenation (A/R) models in vitro with ATO pretreatment and further assessed liver function by histopathologic changes, enzyme-linked immunosorbent assay, cell counting kit-8, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Small interfering RNA (siRNA) for extracellular signal-regulated kinase (ERK) 1/2 was transfected to evaluate the role of ERK1/2 pathway during HIRI, followed by ATO pretreatment. The dynamic process of autophagic flux and numbers of autophagosomes were detected by green fluorescent protein-monomeric red fluorescent protein-LC3 (GFP-mRFP-LC3) staining and transmission electron microscopy. RESULTS:A low dose of ATO (0.75 μmol/L in vitro and 1 mg/kg in vivo ) significantly reduced tissue necrosis, inflammatory infiltration, and hepatocyte apoptosis during the process of hepatic I/R. Meanwhile, ATO obviously promoted the ability of cell proliferation and liver regeneration. Mechanistically, in vitro  studies have shown that nontoxic concentrations of ATO can activate both ERK and phosphoinositide 3-kinase-serine/threonine kinase (PI3K-AKT) pathways and further induce autophagy. The hepatoprotective mechanism of ATO, at least in part, relies on the effects of ATO on the activation of autophagy, which is ERK-dependent. CONCLUSION:Low, non-toxic doses of ATO can activate ERK/PI3K-AKT pathways and induce ERK-dependent autophagy in hepatocytes, protecting liver against I/R injury and accelerating hepatocyte regeneration after partial hepatectomy.

BACKGROUND & AIMS:Hepatic ischemia-reperfusion injury (HIRI) is a critical complication of liver surgery and transplantation that contributes significantly to severe organ failure. GRINA, a calcium-regulating endoplasmic reticulum (ER) protein, plays an essential role in controlling the unfolded protein response; however, its role in HIRI remains unclear. The aim of this study was to investigate the function of GRINA in HIRI and explore its potential as a therapeutic target. METHODS:Liver tissues from patients undergoing hepatectomy, alongside a mouse model of partial HIRI, were used to assess GRINA expression levels. Hepatocyte-specific Grina knockout and transgenic mouse models were generated to explore the effects of GRINA on HIRI. Key markers of inflammation, apoptosis, ER stress, and autophagy were evaluated via real-time PCR, Western blotting, immunohistochemistry, immunofluorescence, and ELISA. RNA sequencing, mass spectrometry, coimmunoprecipitation and ubiquitination assays were used to elucidate the underlying molecular mechanisms. RESULTS:GRINA expression was markedly reduced in hepatocytes from both patients and mice with HIRI, and its expression was inversely correlated with the severity of liver damage. Hepatocyte-specific Grina overexpression mitigated liver injury, the inflammatory response, and hepatocyte apoptosis following HIRI, whereas GRINA deficiency exacerbated these outcomes. Mechanistically, GRINA interacted directly with ATF6 and recruited HRD1 to form a multiprotein complex that catalyzed ATF6 polyubiquitination, thereby promoting its degradation. This process suppressed ER autophagy (ER-phagy), providing cellular protection following HIRI. The inhibition of ATF6 degradation attenuated the protective effects of GRINA in HIRI. CONCLUSIONS:Our study highlights the critical role of the GRINA-HRD1-ATF6 complex in regulating ER stress and autophagy during HIRI. These findings provide new insights into therapeutic strategies to alleviate HIRI. IMPACT AND IMPLICATIONS:Hepatic ischemia-reperfusion injury (HIRI) represents a multifaceted pathophysiological challenge commonly encountered during liver surgeries, yet its underlying molecular mechanisms remain inadequately understood. In this study, we revealed a significant negative correlation between GRINA levels and the severity of liver damage in patients with HIRI. Our findings demonstrate that GRINA alleviates endoplasmic reticulum stress by enhancing HRD1-mediated ubiquitination of ATF6, thereby maintaining calcium homeostasis and inhibiting ER-phagy. This study provides novel insights into the role of GRINA in protecting liver cells under HIRI, offering fresh perspectives for clinical prevention and management strategies for HIRI.

BACKGROUND:To evaluate the prognostic significance of micro-lymphatic invasion (MLI), independent of lymph node metastasis (LNM) and micro-vascular invasion (MVI) in patients with intrahepatic cholangiocarcinoma (ICC). METHODS:We conducted a retrospective cohort study of 137 ICC patients who underwent curative resections between January 2017 and December 2022 in Huashan Hospital. Patients were categorized based on MLI and MVI status, determined by D2-40, α-SMA, CD34, CK19 immunostaining in multi-sites of tumor and para-tumor. Recurrence-free survival (RFS) and overall survival (OS) were compared between groups. RESULTS:The median OS was 34 months, with 1-year, 2-year, and 3-year OS rates of 90.7 %, 69.4 %, and 39.5 %, respectively. Patients with LNM exhibited significantly poorer OS (median 18 months) and RFS (median 7 months) compared to those without LNM (38 vs. 18 months). Furthermore, MLI was associated with reduced OS (24 months for MLI (+) vs. >60 months for MLI (-)) and RFS (12 vs. >60 months). Among patients without LNM, those with MLI(+) exhibited significantly poorer OS and RFS compared to those without MLI, mirroring the poor prognosis of patients with potential LNM. MVI (+) showed a trend towards reduced OS (24 vs. 36 months), and significantly impacted RFS (12 vs. 18 months). Additionally, multivariate analysis identified carcinoembryonic antigen, carbohydrate antigen 19-9, perineural invasion and MLI as independent prognostic factors for OS. For RFS, carbohydrate antigen 19-9, tumor size, perineural invasion and MLI were found to be independent prognostic factors. CONCLUSIONS:The results of the study highlight the critical importance of incorporating MLI into prognostic evaluations.

Hepatic ischemia‒reperfusion injury (HIRI) is a common pathological phenomenon after hepatectomy and liver transplantation. Here, we aim to explore the role of Axin formation inhibitor 1 (Axin1) in HIRI. In this work, we find that the expression of Axin1 is upregulated after HIRI. Cellular experiments confirme that Axin1 knockdown alleviated hypoxia/reoxygenation (H/R)-induced inflammation and apoptosis. Subsequently, we construct a HIRI model based on transgenic hepatocellular-specific Axin1 knockout and overexpression male mice and find that Axin1 deletion alleviated inflammation and apoptosis. Transcriptome sequencing reveal that the genes whose expression differed after Axin1 overexpression are significantly enriched in the PPAR signaling pathway. Furthermore, we demonstrate that Axin1 negatively regulates the expression of PPARβ, thereby activating the NF-κB pathway. Mechanistically, Axin1 binds to PPARβ to enhance the ubiquitination-mediated degradation of PPARβ by the E3 ubiquitin ligase RBBP6. Notably, adenovirus-mediated Axin1 knockdown block I/R damage in mice. Our study results demonstrate that Axin1 exacerbates HIRI by promoting the ubiquitination and degradation of PPARβ, which in turn activates the NF-κB signaling pathway. These results suggest that Axin1 may be a potential therapeutic target for HIRI. Hepatic ischemia reperfusion injury (HIRI) is a common complication after hepatectomy and liver transplantation. Here, the authors show that Axin1 exacerbates HIRI by promoting PPARβ ubiquitination and degradation via E3 ubiquitin ligase RBBP6, activating the NF-κB pathway, and may be a potential therapeutic target.

Hepatic ischemia‒reperfusion injury (HIRI) occurs during liver surgery, contributing to postoperative complications such as liver failure, prolonged hospital stays, and increased morbidity and mortality rates. Yet, the mechanism underlying HIRI remains unclear. Nicotinamide N-methyltransferase (NNMT) facilitates the conversion of nicotinamide into N1-methylnicotinamide (1-MNA) and plays crucial roles in various pathophysiological processes. In this study, we find a decrease in hepatic NNMT expression and serum 1-MNA levels during HIRI. Both NNMT overexpression and exogenous 1-MNA treatment alleviate HIRI in male mice HIRI models and primary hepatocytes H/R models. Mechanistically, NNMT/1-MNA plays key roles in inflammation, apoptosis, and vascular injury during HIRI through the AKT/FOXO1/ANGPT2/JNK axis. Hepatic-specific depletion of NNMT leads to increased ANGPT2 expression and exacerbates HIRI, effects that can be mitigated by ANGPT2 knockdown. Our findings suggest that NNMT/1-MNA/ANGPT2 may regulate HIRI via the JNK signaling pathway. In summary, we present the function of NNMT and its underlying mechanism in liver injury, providing potential new therapeutical strategies for addressing HIRI.