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Tumor-associated macrophages (TAMs) are major components of the tumor microenvironment (TME) which are closely associated with the tumor malignant progression. However, the regulatory mechanisms by which TAMs influence the progression of triple-negative breast cancer (TNBC) remain unclear. Here, we report that hepatic leukemia factor (HLF) acts as a novel oncoprotein in TNBC. We found that HLF was regulated by transforming growth factor-beta1 (TGF-β1) that is secreted by TAMs. Then, HLF transactivated gamma-glutamyltransferase 1 (GGT1) to promote the ferroptosis resistance, thus driving TNBC cell proliferation, metastasis and cisplatin resistance. Reciprocally, IL-6 produced by TNBC cells activated the JAK2/STAT3 axis to induce TGF-β1 secretion by TAMs, thus constituted a feed-forward circuit. The accuracy of TNBC patient prognosis could be improved by employing a combination of HLF and GGT1 values. Thus, our findings document that the interactive dialogue between TNBC cells and TAMs promotes sustained activation of HLF in tumor cells through the IL-6-TGF-β1 axis. Subsequently, HLF promotes the ferroptosis resistance in TNBC cells via GGT1 and ultimately facilitates the malignant tumor progression. Our study provides a potential target for the treatment of TNBC.

Acute myeloid leukemia (AML) patients with FLT3 -ITD mutations were benefit from hematopoietic cell transplantation (HSCT) in the first complete remission. Previous research suggested that newly diagnosed AML patients with high allelic ratio (AR) of FLT3 -ITD have unfavorable survivals, while newly diagnosed AML patients with lower FLT3 -ITD AR and concomitant NPM1 mutations have favorable outcomes. In AML patients with FLT3 -ITD, co-occurrence with DNMT3A , and NPM1 mutations (triple-mutated AML patients) have the worst prognoses, however, it is little known about how these mutations synergize in these triple-mutated AML patients. Here we showed that hepatic leukemia factor ( HLF ) gene was more highly expressed in triple-mutated AML patients than in those without the DNMT3A mutations. We found that HLF gene expressions had significant difference in triple-mutated and FLT3- ITD/ NPM1 AML patients (double-mutated AML patients). Moreover, in DNMT3A mutated AML patients, correlated with high HLF gene expression, which may be itself associated with poor survival rate and drug resistance. Overall our data establish that HLF gene as a novel biomarker in this genetically defined the triple-mutated AML subgroup.

The fusion of human serum albumin with human lactoferrin (hLF‐HSA) exerts strong anti‐migratory effects in human lung adenocarcinoma cells through matrix metalloproteinase 1 (MMP1) downregulation. We demonstrate that hLF‐HSA disrupts organelle pH homeostasis via Na + /H + exchanger 7 (NHE7) upregulation, inducing organelle alkalization in the Golgi apparatus. This organelle dysfunction alters the Golgi‐mediated secretome, leading to MMP1 downregulation and suppression of cell migration. hLF‐HSA‐induced MMP1 downregulation also reverses epithelial‐mesenchymal transition (EMT), further suppressing migration. Additionally, hLF‐HSA‐driven activation of caveolae‐mediated endocytosis (CavME) signaling downregulated MMP1 expression without NHE7 upregulation. These findings highlight that hLF‐HSA–mediated disruption of organelle pH regulation and CavME activation represents a potential strategy to suppress cancer cell migration. Impact statement This work reveals a previously unrecognized link between organelle pH dysregulation and cancer cell migration. By identifying hLF‐HSA as a dual modulator of Golgi function and endocytic signaling, it provides a mechanistic basis for developing novel anti‐metastatic strategies targeting intracellular trafficking rather than cytotoxicity.

Metabolic‐associated fatty liver disease (MAFLD) has become increasingly widespread. The intestine is the primary site of lipid absorption and is important for the homeostasis of lipid metabolism. However, the mechanism underlying the participation of the intestinal tract in the development of MAFLD requires additional investigation. In this study, analysis of the single‐cell transcriptome of intestinal tissue from cynomolgus monkeys found that hepatic leukemia factor (HLF) participated in the genetic regulation of intestinal lipid absorption. Results obtained from normal and intestine‐specific Hlf‐knockout mice confirmed that HLF alleviated intestinal barrier disorders by inhibiting peroxisome proliferator‐activated receptor alpha (PPARα) expression. The HLF/PPARα axis alleviated MAFLD by mediating gut microbiota‐derived extracellular vesicles (fEVs), thereby inhibiting hepatocyte ferroptosis. Lipidomics and functional experiments verified that taurochenodeoxycholic acid (TCDCA), a conjugated bile acid contained in the fEVs, had a key role in the process. In conclusion, intestinal HLF activity was mediated by fEVs and identified as a novel therapeutic target for MAFLD. The specific knockout of intestinal hepatic leukemia factor (HLF) improved metabolic‐associated fatty liver disease (MAFLD) by inhibiting peroxisome proliferator‐activated receptor alpha (PPARα) and restoring the intestinal barrier. Study of the mechanism revealed that the HLF/PPARα axis regulated gut microbiota‐derived extracellular vesicles (fEVs); which, through the gut‐liver cycle, suppressed hepatocyte ferroptosis and reduced hepatic steatosis. Lipidomics and functional assays identified the conjugated bile acid taurochenodeoxycholic acid (TCDCA) as the key driver of the lipid‐lowering effect of fEVs. The findings offer new therapeutic strategies for MAFLD. Highlights Intestinal‐specific lack of hepatic leukemia factor (HLF) can improve metabolic‐associated fatty liver disease (MAFLD). HLF plays a role in fat metabolism regulation through peroxisome proliferator‐activated receptor alpha (PPARα). The HLF/PPARα axis regulates the gut microbiome and influences the composition of gut microbiota‐derived extracellular vesicles (fEVs). The bound bile acid taurochenodeoxycholic acid (TCDCA) is a key regulatory factor for fEVs to improve MAFLD.

Medicinal leeches of the genus Hirudo inhabit large areas of the Palaearctic realm. The distribution range of Hirudo troctina includes the southern Iberian peninsula and the northwestern regions of Africa. H. troctina is used for medical purposes, but only very little is known about the components of its salivary gland secretion. Hirudins, bivalent inhibitors of thrombin, are probably the best known leech-derived bioactive factors. Hirudin-like factors (HLFs) represent another class of salivary gland components that share characteristic genetic and structural markers with hirudins. Hirudin is not a single entity but exists in at least four different variants. However, there are differences among the European members of the genus Hirudo with respect to the actual number of hirudin and HLF genes that are present within their genomes. Here, we describe the identification and molecular cloning of 11 genes that encode for putative hirudin and HLF variants in H. troctina . Three of the genes consist of exons and introns that originate from different “archetype” genes and are likely the result of recombination events. The diversity of hirudin and HLF genes in H. troctina surpasses that of all other European members of the genus Hirudo . The putative hirudin variants and representatives of the HLFs of H. troctina were expressed as recombinant proteins, purified and functionally characterized for their thrombin-inhibiting potencies. Phylogenetic analyses based on hirudin and HLF gene sequences of the leech genera Hirudo , Hirudinaria , and Whitmania supported the hypothesis that hirudins and HLFs diverged early in leech evolution.

Idiopathic orbital inflammation, formerly known as NSOI (nonspecific orbital inflammation), is characterized as a spectrum disorder distinguished by the polymorphic infiltration of lymphoid tissue, presenting a complex and poorly understood etiology. Recent advancements have shed light on the HLF (Human lactoferrin), proposing its critical involvement in the regulation of hematopoiesis and the maintenance of innate mucosal immunity. This revelation has generated significant interest in exploring HLF's utility as a biomarker for NSOI, despite the existing gaps in our understanding of its biosynthetic pathways and operational mechanisms. Intersecting multi-omic datasets—specifically, common differentially expressed genes between GSE58331 and GSE105149 from the Gene Expression Omnibus and immune-related gene compendiums from the ImmPort database—we employed sophisticated analytical methodologies, including Lasso regression and support vector machine-recursive feature elimination, to identify HLF. Gene set enrichment analysis and gene set variation analysis disclosed significant immune pathway enrichment within gene sets linked to HLF. The intricate relationship between HLF expression and immunological processes was further dissected through the utilization of CIBERSORT and ESTIMATE algorithms, which assess characteristics of the immune microenvironment, highlighting a noteworthy association between increased HLF expression and enhanced immune cell infiltration. The expression levels of HLF were corroborated using data from the GSE58331 dataset, reinforcing the validity of our findings. Analysis of 218 HLF-related differentially expressed genes revealed statistically significant discrepancies. Fifteen hub genes were distilled using LASSO and SVM-RFE algorithms. Biological functions connected with HLF, such as leukocyte migration, ossification, and the negative regulation of immune processes, were illuminated. Immune cell analysis depicted a positive correlation between HLF and various cells, including resting mast cells, activated NK cells, plasma cells, and CD8 T cells. Conversely, a negative association was observed with gamma delta T cells, naive B cells, M0 and M1 macrophages, and activated mast cells. Diagnostic assessments of HLF in distinguishing NSOI showed promising accuracy. Our investigation delineates HLF as intricately associated with NSOI, casting light on novel biomarkers for diagnosis and progression monitoring of this perplexing condition.

FLT 3 internal tandem duplication ( FLT3 -ITD) is a frequent mutation in acute myeloid leukemia (AML) and remains a strong prognostic factor due to high rate of disease recurrence. Several FLT3 -targeted agents have been developed, but determinants of variable responses to these agents remain understudied. Here, we investigated the role FLT3 -ITD allelic ratio (ITD-AR), ITD length, and associated gene expression signatures on FLT3 inhibitor response in adult AML. We performed fragment analysis, ex vivo drug testing, and next generation sequencing (RNA, exome) to 119 samples from 87 AML patients and 13 healthy bone marrow controls. We found that ex vivo response to FLT3 inhibitors is significantly associated with ITD-AR, but not with ITD length. Interestingly, we found that the HLF gene is overexpressed in FLT3 -ITD + AML and associated with ITD-AR. The retrospective analysis of AML patients treated with FLT3 inhibitor sorafenib showed that patients with high HLF expression and ITD-AR had better clinical response to therapy compared to those with low ITD-AR and HLF expression. Thus, our findings suggest that FLT3 ITD-AR together with increased HLF expression play a role in variable FLT3 inhibitor responses observed in FLT3 -ITD + AML patients.

The presence of cancer stem cells (CSCs) contributes significantly to treatment resistance in various cancers, including head and neck squamous cell carcinoma (HNSCC). Despite this, the relationship between cancer stemness and immunity remains poorly understood. In this study, we aimed to identify potential immunotherapeutic targets and sensitive drugs for CSCs in HNSCC. Using data from public databases, we analyzed expression patterns and prognostic values in HNSCC. The stemness index was calculated using the single-sample gene set enrichment analysis (ssgsea) algorithm, and weighted gene co-expression network analysis (WGCNA) was employed to screen for key stemness-related modules. Consensus clustering was then used to group samples for further analysis, and prognosis-related key genes were identified through regression analysis. Our results showed that tumor samples from HNSCC exhibited higher stemness indices compared to normal samples. WGCNA identified a module highly correlated with stemness, comprising 187 genes, which were significantly enriched in protein digestion and absorption pathways. Furthermore, we identified sensitive drugs targeting prognostic genes associated with tumor stemness. Notably, two genes, HLF and CCL11, were found to be highly associated with both stemness and immunity. In conclusion, our study identifies a stemness-related gene signature and promising drug candidates for CSCs of HNSCC. Additionally, HLF and CCL11, which are associated with both stemness and immunity, represent potential targets for immunotherapy in HNSCC.