This study investigates the impact of tryptophan substitution on the properties of the Medisin family peptide MS-PT. By substituting hydrophobic amino acids in MS-PT1 with tryptophan, a series of derivative peptides were synthesized. Among them, the 7W peptide stood out with its unique N-terminal random curl and α-helix structure. In vitro, 7W effectively inhibited the secretion of pro-inflammatory cytokines like IL-6 and TNF-α in LPS-induced Membrane-Proximal Macrophages (MPMs) by blocking the MAPK/NF-κB signaling pathway. It also exhibited stronger antimicrobial activity against Gram-positive bacteria compared to the parent peptide MS-PT1, with good safety as indicated by a low hemolysis rate. In vivo, in the CLP-induced sepsis mouse model, 7W alleviated lung and liver injury, suppressed the expression of inflammatory factors in serum and tissues, and had a relatively long plasma half-life of 46.8 h. Mechanistically, 7W interacted preferentially with bacterial mimic membranes and LPS, and its anti-inflammatory effect might be mediated by binding to TLR4. These findings not only clarify the role of tryptophan substitution in modulating peptide properties but also offer a new strategy for the development of multifunctional antimicrobial peptides, suggesting that 7W has great potential as a therapeutic agent for sepsis and other inflammatory diseases.

Thyroid cancer (TC) is the most prevalent endocrine malignancy, with a rising incidence necessitating safer treatment strategies to reduce overtreatment and its side effects. Xiaoyao Powder (XYP), a widely used herbal formula, shows promise in treating TC. This study aims to investigate the mechanisms by which XYP may affect TC.

The components of XYP were identified through database retrieval, and targets related to TC were collected to construct a target network for key screening. GEO dataset samples analyzed immune cells and identified significantly differentially expressed core genes (SDECGs). Based on SDECG expression and clustering, samples were classified for comparison. WGCNA was employed to identify gene modules linked to clinical characteristics. ML models screened characteristic genes and constructed a nomogram validated using another GEO dataset. MR methods explored causal relationships between genes and TC.

The top ten active components of XYP were identified, along with 27 SDECGs that exhibited significant differences in immune cell infiltration between TC patients and normal controls. The nomogram effectively predicted TC risk, validated through ROC curves. Key characteristic genes included SMIM1, PPP1R16A, KIAA1462, DNAJC22, and EFNA5.

XYP may treat TC by regulating SMIM1, PPP1R16A, KIAA1462, DNAJC22, EFNA5, and associated immune pathways; this provides theoretical support for its potential mechanisms.

Actinobacillus pleuropneumoniae (A. pleuropneumoniae), a porcine respiratory tract pathogen, causes porcine pleuropneumonia. Porcine alveolar macrophages (PAMs) play a crucial role during A. pleuropneumoniae infection. Amyloid precursor protein (APP) can be cleaved by β- and γ-secretase to produce β-amyloid (Aβ). APP and Aβ are associated with the inflammatory response. They activate microglia and astrocytes to secrete IL-1β, IL-6, and other cytokines. In this study, we found that during the interaction between A. pleuropneumoniae and PAMs, the two-component system CpxAR upregulates wecA expression, increasing lipopolysaccharide (LPS) production. LPS promotes APP production and cleavage to generate Aβ. The Aβ activates NF-κB, leading to increased IL-1β expression. We hypothesize that A. pleuropneumoniae infection of PAMs regulates APP production and cleavage to control Aβ levels. Different quantities of Aβ induce PAMs to produce varying amounts of cytokines, leading to different pathological processes in porcine pleuropneumonia.

Liver fibrosis is a reversible pathophysiological condition characterized by excessive extracellular matrix deposition that can progress to cirrhosis and liver failure if left untreated. Taurine, a sulfur-containing amino acid, protects the liver from damage. However, the effects of taurine on liver fibrogenesis have not been completely elucidated. In this study, we used amino acid metabolomics, gene expression microanalysis, and single-cell RNA sequencing (scRNA-seq) to investigate the roles of taurine, formyl peptide receptor 2 (Fpr2), and proinflammatory macrophages in liver fibrosis in human fibrotic sections and two distinct mouse models of liver fibrosis. Taurine transporter SLC6A6 wild-type and knockout littermate models and critical element inhibitors were also used. We found that taurine levels were significantly reduced in both human and murine fibrotic sections and that exogenous taurine supplementation alleviated fibrosis via SLC6A6. Furthermore, gene expression microarray analysis and scRNA-seq analyses demonstrated that exogenous taurine mitigated liver fibrosis, mainly by regulating Fpr2-related macrophage status. WRW4-mediated inhibition of Fpr2 ameliorated M1 macrophage polarization and alleviated liver fibrosis. Additionally, exogenous taurine suppressed Fpr2-modulated macrophage M1 polarization and the production of associated proinflammatory cytokines by repressing NF-κBp65 phosphorylation; moreover, SLC6A6 deficiency or treatment of liver fibrosis mouse models with an NF-κB inhibitor, BAY, impaired this protective effect of taurine. Therefore, taurine exerts a protective effect against liver fibrosis by repressing Fpr2/NF-κBp65-regulated macrophage M1 polarization, highlighting its potential therapeutic agent.

Macrophages represent a crucial cell type within the immune system, exhibiting significant adaptability that allows for the transformation into various phenotypes in response to their surrounding environment. This review investigates the characteristics of various macrophage phenotypes and their functional roles in disease pathogenesis and resolution. The M1 phenotype, recognized for its inflammatory attributes, plays a pivotal role in combating infections and tumors; however, it may also contribute to tissue injury, persistent inflammation, and the pathogenesis of autoimmune and inflammatory diseases. Conversely, the M2 phenotype is associated with anti-inflammatory activities and tissue repair processes. But this is not the end of the story and researches illustrated novel phenotypes that may provide new approaches and therapeutic opportunities. Recent progress in characterizing distinct macrophage phenotypes has enabled the development of innovative therapeutic strategies for chronic inflammatory conditions, autoimmune disorders, and cancers. This review underscores the critical role of macrophage polarization, illustrating how various stimuli can influence macrophage fate and modify their responses. Additionally, it explores the implications of macrophage plasticity on disease progression and treatment efficacy. A comprehensive understanding of these dynamics is essential for the advancement of targeted immunotherapies, which possess the potential to transform treatment strategies for a variety of medical conditions.

With the increasing prevalence of diabetes, diabetic foot ulcers (DFUs) have become a global health challenge, significantly impacting patients' quality of life and placing a substantial burden on healthcare systems. Among various immune cell subsets, M2-polarized macrophages play a pivotal role in tissue repair and inflammation resolution. This study uses single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing to comprehensively investigate the role of the TFAP2A-LIFR-Hippo-YAP signaling axis in regulating macrophage M2 polarization and its critical function in DFU wound healing. Through scRNA-seq analysis, we identified nine major immune cell subsets in DFU samples, with macrophages emerging as key regulatory cells. In vitro experiments further confirmed that TFAP2A promotes macrophage M2 polarization (evidenced by increased expression of the M2 marker ARG1) and ameliorates endothelial dysfunction by enhancing tube formation, improving migration capacity, and upregulating relevant proteins such as VCAM-1. Moreover, TFAP2A serves as a central regulatory gene for macrophage function in DFU by upregulating LIFR expression and activating the Hippo-YAP signaling pathway, thereby inducing M2 polarization and mitigating endothelial dysfunction. Mouse model experiments further demonstrated that the TFAP2A-LIFR-Hippo-YAP signaling axis accelerates DFU wound healing through the induction of macrophage M2 polarization. This study unveils a novel immunoregulatory role of TFAP2A in DFU and provides a promising therapeutic target for the treatment of chronic diabetic wounds.NEW & NOTEWORTHY This study provides unprecedented insights into diabetic foot ulcer healing by demonstrating the novel immunoregulatory role of the TFAP2A-LIFR-Hippo-YAP signaling axis. Leveraging single-cell and bulk transcriptomics, we identify TFAP2A as a crucial regulator of macrophage M2 polarization, essential for wound healing and angiogenesis. These findings offer valuable mechanistic understanding and present TFAP2A as a promising therapeutic target for improving outcomes in chronic diabetic wounds.

The roots of Shuteria involucrata (Wall.) Wight & Arn., known as "Tong-qian-ma-huang" in Dai folk medicine in China, are renowned for their efficacy in treating asthma. Despite the use of S. involucrata has been reported as ameliorating respiratory diseases, its mechanism of action remains unclear. This work described the effect of ethyl acetate extract of S. involucrate (SSE) on allergic asthma and its potential mechanism of action was assessed. Ovalbumin was used in vivo to establish a BALB/c asthma mouse model. Lipopolysaccharide was used in vitro to stimulate the human macrophage cell line THP-1 to establish an inflammatory model. In vivo and in vitro experiments showed that SSE effectively ameliorated pathological symptoms and attenuated airway inflammation and cellular inflammation in allergic asthma mice, with a mechanism of action potentially associated to the inhibition of the TLR4/NF-κB signaling pathway.

Cancer immunotherapy has evolved into a new generation strategy in the field of anti-tumor treatment. Polysaccharides derived from Traditional Chinese Medicine (TCM) are gaining recognition as powerful immunomodulators in cancer therapy, noted for their multi-target and multi-pathway actions. Owing to their beneficial properties such as water solubility, biocompatibility, and chemical structure modifiability, TCM polysaccharides can also serve as carriers for hydrophobic drugs in the development of innovative drug delivery systems, enhancing synergistic antitumor effects. In this article, we summarize the diverse mechanisms of immunoregulation by TCM polysaccharides in tumor therapy. The applications of these polysaccharides as both active ingredients and drug carriers within nanodelivery systems for cancer immunotherapy are also introduced. Additionally, extensive research on TCM polysaccharides in clinical settings has been collected. Furthermore, discussions are presented on the development prospects and challenges faced by these polysaccharides in the field of tumor immunotherapy. Our goal is to improve researchers' comprehension of TCM polysaccharides in cancer immunotherapy, providing promising strategies to optimize cancer treatment and benefit diverse patient populations.

Stromal vascular fraction (SVF) cells and micro-fragmented adipose tissue (MFAT) have potential for treating knee osteoarthritis (OA), but their efficacy has not been compared. This study aimed to compare the clinical outcomes of SVF and MFAT for knee OA. We hypothesized that SVF provides stronger short-term effects, while MFAT offers more sustained benefits.

A retrospective single-center cohort study was conducted on patients with knee OA, with 36 SVF and 36 MFAT cases selected through propensity score matching between September 2017 and February 2022. Patients with KL grades I-IV varus knee OA, significant pain (VAS ≥40), and functional impairment despite conservative treatments were included. Those with knee trauma, severe bony defects, infections, genu valgus, osteonecrosis, rheumatoid arthritis, or severe deformities were excluded. Clinical outcomes were assessed using the visual analog scale, KOOS, knee range of motion, extension/flexion strength, and MRI T2 mapping.

SVF and MFAT groups demonstrated significant improvements in VAS (p < 0.01 for both groups). Both groups showed notable improvements in extension angle, extension/flexion muscle strength, and KOOS, with no significant differences between them. However, the MFAT group demonstrated significantly greater improvement in flexion angle compared to the SVF group (p = 0.03). No serious adverse events were reported. T2 mapping showed significant improvements in cartilage quality in both groups, with the MFAT group demonstrating superior improvements in specific lateral regions. Responder rate in SVF group initially improved but declined over time; however, the MFAT group showed sustained improvement from six months onward.

T2 mapping revealed that MFAT had better cartilage preservation than that of SVF cells in less-loaded areas, with a potentially longer-lasting therapeutic effect. These findings offer important insights for clinicians to tailor treatment strategies based on patient needs and disease progression.

Streptococcus equi subsp. zooepidemicus (SEZ) is an important pathogen which is responsible for a wide range of diseases in various species. Macrophages are professional phagocytes that can engulf microorganisms and trigger responses leading to microbial death. Caspase-1 is considered as a proinflammatory factor that mediates antibacterial response to protect hosts from bacteria. Here, we revealed a novel role of Caspase-1 in mice against SEZ. Through both in vitro and in vivo infection assays, we demonstrated that the maturation and secretion of the cytokine IL-1β are critically dependent on Caspase-1 activation. The Caspase-1 deficient mice displayed attenuation of bactericidal activity against SEZ, mainly by decreasing the accumulation of macrophage. In addition to the recruitment of macrophages, deficiency of Caspase-1 also impaired the phagocytosis of SEZ by macrophages. Our study demonstrated that Caspase-1 is critical for mice to defense against SEZ depending on the recruitment and phagocytosis of macrophage.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP), contributing significantly to global disability and productivity loss. Its pathogenesis involves complex processes, including inflammation, cellular senescence, angiogenesis, fibrosis, neural ingrowth, and sensitization. Emerging evidence highlights macrophages as central immune regulators infiltrating degenerated discs, with macrophage polarization implicated in IVDD progression. However, the mechanisms linking macrophage polarization to IVDD pathology remain poorly elucidated.

A comprehensive literature review was conducted by searching major databases (PubMed, Web of Science, and Scopus) for studies published in the last decade (2014-2024). Keywords included "intervertebral disc degeneration," "macrophage polarization," "inflammation," "senescence," and "therapeutic strategies." Relevant articles were selected, analyzed, and synthesized to evaluate the role of macrophage polarization in IVDD.

Macrophage polarization dynamically influences IVDD through multiple pathways. Pro-inflammatory M1 macrophages exacerbate disc degeneration by amplifying inflammatory cytokines (e.g., TNF-α, IL-1β), promoting cellular senescence, and stimulating abnormal angiogenesis and neural ingrowth. In contrast, anti-inflammatory M2 macrophages may mitigate degeneration by suppressing inflammation and enhancing tissue repair. Therapeutic strategies targeting macrophage polarization include pharmacological agents (e.g., cytokines, small-molecule inhibitors), biologic therapies, gene editing, and physical interventions. Challenges persist, such as incomplete understanding of polarization triggers, lack of targeted delivery systems, and limited translational success in preclinical models.

Macrophage polarization is a pivotal regulator of IVDD pathology, offering promising therapeutic targets. Future research should focus on elucidating polarization mechanisms, optimizing spatiotemporal control of macrophage phenotypes, and developing personalized therapies. Addressing these challenges may advance innovative strategies to halt or reverse IVDD progression, ultimately improving clinical outcomes for LBP patients.

Thoracic tumours represent a significant proportion of malignant cancers. While radiotherapy (RT) improves prognosis, it can also lead to side effects such as radiation-induced pneumonitis (RP). Since SIRT6 is involved in DNA repair, energy metabolism and inflammation, this study aims to investigate the expression of SIRT6 in lymphocytes as a potential biomarker and therapeutic target for RP. This study included 170 patients diagnosed with thoracic tumours, all of whom underwent thoracic RT. RP was evaluated and classified as severe RP (SRP) and lower as non-severe RP (NSRP). Analyses were performed using SPSS version 26.0 and the R. Among 170 patients in this study, 124 developed NSRP, and 46 experienced SRP. The univariate analysis showed that SIRT6 expression (cOR, 0.33, 95%CI, 0.18-0.97 before RT and 0.31, 0.19-0.98 after RT), clinical factors, dosimetric parameters and haematological/serological parameters were associated with SRP before and after RT. Our multivariable logistic regression showed that SIRT6 expression was significantly associated with risk of SRP before (aOR, 0.32, 95%CI, 0.15-0.96) and after RT (aOR, 0.32, 95%CI, 0.18-0.99) after adjustment with other confounders. Moreover, the receiver operating characteristic curve analysis revealed that the combined multivariable model exhibited superior predictive capability compared to any single predictor (overall AUC, 0.93, 95%CI, 0.90-0.97 before RT and AUC, 0.91, 95%CI, 0.87-0.96 after RT). The expression of SIRT6 alone or in combination with other risk factors was associated with an increased risk of SRP, suggesting a novel approach for the prevention and treatment of radiation pneumonitis in clinical practice.

Acute lung injury (ALI), a severe pulmonary disorder that poses a significant threat to life, is closely associated with macrophage ferroptosis and polarization. Lipocalin 2 (LCN2) has been previously reported to be implicated in the pathogenesis of ALI. However, the specific role of LCN2 in macrophage ferroptosis and polarization remains undetermined. Lipopolysaccharide (LPS) was used to establish a mouse model of ALI and also to stimulate mouse RAW264.7 cells. H&E staining was used for histopathologic evaluation, and immunohistochemistry analysis was used to determine the 4-HNE-positive cells. The secretion levels of TNF-α, IL-6, and IL-1β were assessed by ELISA. Gene and protein expression assays were performed using quantitative PCR and immunoblotting. The levels of MDA, GSH, ROS, and lipid ROS were detected to evaluate the alteration in ferroptosis. CD86+ and CD206+ cells were quantified by flow cytometry. The relationship between LCN2 and interferon regulatory factor 7 (IRF7) was confirmed by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. LCN2 expression was upregulated in the lungs of LPS-induced ALI mice and LPS-stimulated RAW264.7 cells. In LPS-induced ALI mice, the depletion of LCN2 alleviated lung injury and ferroptosis, and also inhibited inflammation and macrophage M1 polarization. In LPS-stimulated RAW264.7 cells, the depletion of LCN2 suppressed ferroptosis, inflammation, and M1 polarization. Mechanistically, IRF7 enhanced LCN2 transcription in RAW264.7 cells by binding to its promoter region. More importantly, the silencing of IRF7 inhibited ferroptosis and M1 polarization in LPS-stimulated RAW264.7 cells by downregulating LCN2. Taken together, the IRF7/LCN2 cascade enhances the ferroptosis and M1 polarization of LPS-stimulated macrophages, thereby exacerbating ALI. Anti-IRF7 and anti-LCN2 therapies might potentially be exploited for the prevention and treatment in ALI.

Acute lung injury (ALI) induced by sepsis is a serious life-threatening disease, one of its characteristics is the polarization of macrophages. Circ_0008285 has been found to be associated with various diseases. In this study, we detected the regulatory role and mechanism of circ_0008285 in sepsis-induced ALI. RAW264.7 cells treated with LPS and C57BL/6 male mice were used to construct in vitro and in vivo models, respectively. Through A series of experiments such as qRT-PCR, Western blot, CCK-8, flow cytometry, dual-luciferase reporter experiment, HE staining and TUNEL staining, the role of circ_0008285 in sepsis-induced ALI was explored. In LPS-induced RAW264.7 cell, circ_0008285 and MAPK14 were over-expressed, but miR-375 was low-expressed compared with control. The levels of IL-1β, IL-6, TNF-α, iNOS and CD86 were reduced, but CD206 and Arg1 expression were enhanced both in vitro and in vivo after knockdown of circ_0008285. In TC-1 cell co-cultured with LPS+sh-circ_0008285 cells, the viability was increased and the apoptosis level was decreased compared with LPS+sh-NC. Circ_0008285 was the sponge of miR-375, and MAPK14 was the downstream target of miR-375. The injury score, W/D ratio, MPO level and apoptosis level in lung tissue were decreased after knockdown of circ_0008285. Moreover, the total protein, neutrophils and macrophages in BALF were increased. Collectively, this study identified that circ_0008285 could sponge miR-375 to influence MAPK14 expression, and then regulate macrophage polarization of sepsis-induced ALI, which provided new insights for the treatment of sepsis-induced ALI.

Macrophages are essential for the proliferation and spread of Toxoplasma gondii. Modulating macrophage activation to improve the inflammatory environment is an effective approach for disease treatment. However, the molecular mechanism through which T. gondii alters macrophage function remain unknown. Based on transcriptomic data analysis of various macrophage types infected with T. gondii, current research revealed differences in the regulation of macrophage functions among strains with different virulence: RH was primarily involved in cell cycle regulation, ME49 was associated with cAMP signaling, and CEP mainly participated in ion channel activity. All three T. gondii strains were involved in regulating immune response activation, including leukocyte adhesion and the MAPK signaling pathway. Nineteen shared DEGs associated with macrophage phagocytosis or polarization were identified through the GeneCards database, and PPI analysis confirmed Il6 as the hub gene in the regulatory network. In vivo and in vitro experiments showed that the YZ-1 strain significantly regulated the expressions of eight DEGs (Il6, Rel, Cd83, Myc, Adora2b, Egr2, Gja1 and Nr4a2), and promoted macrophage phagocytic activity and induced M1 polarization, confirming a significant correlation with Il6. This study revealed the dissimilarities and commonalities in macrophage function regulated by T. gondii strains of different virulence, and identified key molecules involved in the regulation of macrophage phagocytosis and polarization during T. gondii infection. This is crucial for identifying potential drug targets against T. gondii and provides a new perspective on the etiopathogenesis and therapeutic approaches for toxoplasmosis.

Lung cancer exhibits high mortality and incidence rates, with tumor-associated macrophages (TAMs) serving as critical contributors to cancer progression. This study investigates the unexplored mechanistic role of HRD1-an E3 ubiquitin ligase implicated in cancer - in orchestrating TAM polarization to affect lung cancer pathogenesis.

HRD1 expression in lung cancer using TCGA database and validated its impact via IHC. THP-1 cells and macrophages isolated from murine tumor tissues via magnetic bead sorting were transfected with the oe-HRD1 plasmid, followed by flow cytometry, ELISA, and RT-qPCR assays to investigate HRD1's regulatory effects on macrophage polarization and function. Co-IP was employed to investigate interactions between USP7 and HRD1/PD-L1, while Immunofluorescence elucidated underlying mechanisms.

HRD1 was highly expressed in lung cancer and promotes tumor growth in tumor-bearing mice and proliferation in THP-1 cells. Strikingly, both in vivo and in vitro overexpression of HRD1 drove macrophage M2 polarization. Mechanistically, USP7 interacted independently with HRD1 and PD-L1, while HRD1 binding to USP7 facilitated PD-L1 ubiquitination. Furthermore, HRD1 overexpression upregulated USP7 expression, thereby enhancing M2 polarization.

HRD1 promotes lung cancer progression by regulating TAM M2 polarization via USP7, offering novel therapeutic targets and diagnostic perspectives for early-stage lung cancer intervention.

Therapeutic mRNA vaccines are limited in inducing tumor shrinkage in advanced cancers due to their inability to overcome immune-suppressive mechanisms within tumors. In this study, we developed an HPV-immunogen-expressing oncolytic virus (OV) using HSV-1 for HPV-related cancer treatment. A mouse syngeneic tumor model evaluates the effectiveness of intratumoral OV application for E6+E7+ tumors. Comparative analysis of OV and mRNA vaccines reveals distinct mechanisms in tumor treatment. Single-cell RNA sequencing and flow cytometry show that OV enhances cytotoxic T cell infiltration, polarizes neutrophils and macrophages toward anti-tumor phenotypes, and promotes immune activation within the tumor. In contrast, the mRNA vaccine more effectively activates peripheral antigen-specific T cell responses. A heterologous prime-boost strategy using the mRNA vaccine to prime systemic T cells, followed by OV therapy to direct these cells into the tumor, leads to significant tumor regression. This combination optimizes both systemic and intratumoral immune responses for advanced HPV-related cancers.

The incidence of allergic diseases has been increasing annually, severely affecting the quality of life of patients. With the growing recognition of traditional medicine, acupuncture, an ancient Chinese therapeutic method, has gradually gained attention for its potential in immune modulation. Studies have shown that macrophages play a crucial role in the development of allergic diseases, and acupuncture may influence allergic reactions by modulating the function of macrophages. This article aims to systematically evaluate the regulatory effects of acupuncture on macrophages in allergic diseases and the corresponding mechanisms. It analyzes existing research findings and explores the clinical application prospects of acupuncture in this context. By understanding how acupuncture affects the activation, secretion, and role of macrophages in immune responses, we hope to provide new insights and directions for the treatment of allergic diseases.

The enhanced M1 macrophage activation and proportion significantly promote the progression of renal fibrosis in the unilateral ureteral obstruction (UUO) model, while the underlying mechanisms need to be further studied. Here, we examined whether or not endoplasmic reticulum (ER) stress contributed to M1 macrophage activation and the mechanisms in this process. In the UUO mouse model, the proportion of M1 macrophages could be significantly increased in the early renal fibrosis, with the ER stress activated. The inhibitor of ER stress (4-PBA) significantly suppressed the activation of M1 macrophages and alleviated the renal fibrosis in the UUO mouse model. Furthermore, the renal fibrosis could be relieved after the administration of IRE1α inhibitor (4μ8C), with the downregulation of ER stress and M1 macrophage activation. Mechanistically, ER stress-enhanced activation of M1 macrophages was regulated through the IRE1α/XBP1s-p38 MAPK pathway. IRE1α-deficient macrophages could alleviate the renal fibrosis in the UUO mouse model. Thus, our findings suggest that the ER stress pathway regulates M1 macrophage activation in the UUO model, which provides a novel therapeutic approach for renal fibrosis.

Acute Lung Injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are major threats to human health, characterized by high mortality rates and a lack of effective treatments. Given the significant role of an over-activated inflammatory response and macrophage polarization in the development of ALI, and the unknown effect of vitamin E in this context, our study aimed to explore vitamin E's potential in alleviating ALI. We established an ALI mouse model by intratracheal instillation of LPS and isolated BMDMs for in-vitro experiments. Results indicated that vitamin E treatment significantly reduced LPS-induced lung injury, as shown by decreased lung wet/dry weight ratio, lower levels of pro-inflammatory factors in bronchoalveolar lavage fluid, and improved mouse survival rates. Vitamin E also alleviated oxidative stress by modulating oxidative and reducing products. Mechanistically, it activated the AMPK signal, upregulated NRF2, scavenged reactive oxygen species, inhibited the NF-κB signal pathway, and regulated macrophage polarization towards the anti-inflammatory M2 phenotype while suppressing the pro-inflammatory M1 polarization. In conclusion, vitamin E may serve as a potential adjuvant treatment for ALI through the AMPK/NRF2 signaling axis, although further research on optimal dosage and combination therapies is needed.

Milk-derived extracellular vesicles (MEV) have received increasing attention due to their physiological benefits for newborn growth and development. However, their physiological characteristics and immunomodulatory capacities during lactation remain unclear. In this study, we isolated MEV from porcine milk at day 1, week 1, week 2, and week 3 after parturition and compared their differences by common EV characterization, showing the higher concentration and smaller mean size of MEV from colostrum. Porcine MEV could be internalized by RAW264.7 macrophages and functionally deliver immune-related microRNAs (miRNAs). Furthermore, MEV promoted macrophage polarization toward the M2-like phenotype and exerted anti-inflammatory effects in vitro. Mice models with sepsis also displayed that MEV suppressed the secretion of pro-inflammatory cytokines in serum and drove an anti-inflammatory M2-like phenotype of the spleen, ultimately weakening immune responses. Especially, MEV from colostrum exhibited the most robust effects on immunoregulation. Overall, this study provides valuable information for MEV secretion patterns and their differences in immunomodulatory bioactivities.

The pathogenesis of chronic subdural hematoma (CSDH) has traditionally been associated with inflammation, but the efficacy of anti-inflammatory drug therapy is limited. Recent literatures suggest that immune dysregulation rather than sole inflammation, plays a vital role in the development of CSDH. In this study, the dynamics of macrophage polarization were explored to elucidate changes in immune status during CSDH evolution. Nakaguchi computerized tomography (CT) classification method was employed to categorize CSDH into four types, including homogeneous, laminar, separated and trabecular subtypes. Samples from the hematoma cavity were collected. The percentages of M1 and M2 macrophages and the M1/M2 proportion were determined by flow cytometry. The M1-related inflammatory (IL-1β, IL-6, IL-12, and TNF-α) and M2-related anti-inflammatory factors (IL-4, IL-10, IL-13, and TGF-β) were measured by ELISA. The relationship among CT subtypes, macrophage polarization and recurrence were evaluated by univariate and multivariate logistic regression analyses. A nomogram was established to score significant factors, and the bootstrap method was used for internal validation to calculate the concordance index (C-index) and generating calibration plots. A total of 127 patients with CSDH were included, among which 28 cases (22.04%) experienced recurrence within three months post-surgery. Significant differences were found in the percentages of M1 and M2 macrophages, the M1/M2 ratio, and related cytokines among different subtypes in CT classifications (P < 0.001). As CSDH evolved according to different CT subtypes, M1 macrophages gradually decreased, while M2 macrophages significantly increased, accompanied by a downregulation of the M1/M2 ratio. The similar changes were found in M1-related inflammatory cytokines (IL-1β, IL-6, IL-12, and TNF-α) and M2-related anti-inflammatory cytokines. Additionally, compared to the non-recurrence group, the recurrence group had higher percentages of M1 and M1/M2 ratio, but lower percentages of M2 (P < 0.05). LASSO regression analysis identified the dichotomized Nakaguchi CT classification, degree of brain atrophy, postoperative drainage volume, and hematoma volume were independent risk factors of recurrence (P < 0.05). Based on this, the established nomogram prediction model showed an AUC of 0.898, indicating good predictive efficacy and accuracy. The study demonstrated that the immune status within the hematoma cavity shifts from an inflammatory to an anti-inflammatory state during CSDH progression. Furthermore, it was found that altered immune balance gives rise to CSDH evolution and recurrence following surgery instead of inflammation itself.

Osteoarthritis (OA) is a common joint disorder that causes significant disability. Previous studies suggested that the predominance of M1 macrophages (MΦs) exacerbates inflammation and cartilage degradation in OA, suggesting that shifting the polarization toward M2 MΦs could be a promising therapeutic strategy. We recently developed CRISPRa-engineered macrophages, termed Elite MΦs, that express IL-10 and maintain a stable M2 phenotype. However, achieving effective and sustained delivery of these cells to the OA joint remains a challenge. In this study, we synthesized two injectable aldehyde hyaluronic acid-based hydrogels, CHO/CDH and ACHO/CDH hydrogels, to serve as Elite MΦ delivery platforms. Comprehensive analyses identified the ACHO/CDH hydrogel as superior due to its enhanced suitability for encapsulating and delivering Elite MΦs. When loaded with Elite MΦs, the ACHO/CDH hydrogel was able to not only localize Elite MΦs but also enhance their anti-inflammatory and reparative effects. Furthermore, intra-articular injection of the Elite MΦ-loaded ACHO/CDH hydrogel in an OA mouse model resulted in notable improvements in the joint's cellular environment, alleviating cartilage degradation and synovial inflammation. These results highlight the ability of the ACHO/CDH hydrogel to rebalance the inflammatory imbalance and promote cartilage repair. This approach not only targets the underlying inflammatory processes more directly than traditional therapies but also harnesses the regenerative potential of macrophages, offering a transformative strategy for OA management.

Facial nerve injury (FNI), hindered by hypoxic microenvironments limiting Schwann cell (SCs) repair potential, remains a therapeutic challenge. We developed light-responsive Chlorella hydrogels (C-Gel) to modulate oxygen release and inflammation. In vitro, light-activated C-Gel enhanced RSC96 SC proliferation, migration, and secretion while reducing reactive oxygen species (ROS), hypoxia-inducible factor-1α (HIF-1α), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). It also shifted macrophage polarization from pro-inflammatory M1 (inducible nitric oxide synthase (iNOS)+/TNF-α+) to anti-inflammatory M2 (arginase-1 (Arg-1)+/IL-10+), with M2-conditioned mediumboosting SCs production of neurotrophic factors (nerve growth factor, NGF; glial cell line-derived neurotrophic factor, GDNF), adhesion molecules (neural cell adhesion molecule-1, NCAM-1), regeneration-associated proteins (c-JUN), and myelin components (myelin basic protein, MBP; myelin-associated glycoprotein, MAG). In vivo, C-Gel-light therapy improved behavioral recovery in FNI rats, suppressed inflammation (ROS/HIF-1α/TNF-α), and enhanced SC-mediated remyelination (S100 calcium-binding protein, S100; neurofilament 200, NF200). RNA sequencing identified upregulated phosphoinositide 3-kinase-protein kinase (PI3K-Akt) and calcium ion (Ca²+) signaling pathways. This oxygen-regulating, immunomodulatory biomaterial offers a dual-action strategy to advance FNI rehabilitation by synergistically optimizing the regenerative microenvironment.

Asthma is a chronic inflammatory disease characterized by airway remodeling and immune dysregulation. This study aimed to explore the mechanisms by which M2 macrophage-derived exosomes (M2Φ-Exos) regulate airway inflammation in asthma by modulating epithelial cell proliferation and apoptosis.

M2Φ-Exos were extracted and characterized by morphology, size, and marker protein expression. In vitro, the effects of M2Φ-Exos on House Dust Mites (HDM)-stimulated mouse lung epithelial cells (MLE-12s) were evaluated using western blotting to analyze Proliferating Cell Nuclear Antigen (PCNA), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase-3 expression. In vivo, M2Φ-Exos were administered to HDM-induced asthmatic mice to assess their impact on airway inflammation, epithelial remodeling, and proliferation-apoptosis balance using immunohistochemistry, immunofluorescence, and western blotting. Cytokine levels in lung tissue and bronchoalveolar lavage fluid (BALF) were measured by qRT-PCR and ELISA.

M2Φ-Exos displayed typical cup-shaped morphology, an average diameter of 115.5 nm, and expressed marker proteins CD9, TSG101, and CD63. MLE-12 cells internalized M2Φ-Exos, leading to reduced abnormal proliferation and apoptosis in HDM-stimulated cells. In asthmatic mice, M2Φ-Exos alleviated airway inflammation and epithelial thickening while reducing PCNA, cleaved caspase-3, and Bax levels and increasing Bcl-2 expression. M2Φ-Exos suppressed pro-inflammatory cytokines (IL-4, IL-5, IL-13) and Transforming growth factor (TGF)-β, while enhancing anti-inflammatory cytokine IFN-γ and IL-10.

These findings demonstrate that M2Φ-Exos regulate the imbalance in epithelial proliferation and apoptosis in asthma, reducing inflammation and mitigating tissue remodeling, and provide new insights into potential therapeutic strategies for asthma management.

Phagocytosis is a key process in human innate immune response. Human macrophages are important phagocytes engulfing and neutralizing pathogens and cell debris. In addition, they modulate the inflammatory process by releasing cytokines and lipid mediators. However, the link between oxylipins and phagocytosis in different macrophage phenotypes remains poorly understood. In order to better understand the link between phagocytosis and the arachidonic acid (ARA) cascade, we established a phagocytosis assay in primary human 'inflammatory' M1- and 'anti-inflammatory' M2-like macrophages from peripheral blood mononuclear cells (PBMC), representing extremes of macrophage phenotypes. The branches of the ARA cascade were investigated by quantitative targeted proteomics and metabolomics. M1-like macrophages show a higher abundance of cyclooxygenase (COX)-2 and its products particularly after LPS stimulus compared to M2-like macrophages. LPS increased phagocytosis in M2-like, but not in M1-like macrophages. We demonstrate that the COX product prostaglandin E2 (PGE2) modulates the differential effects of LPS on phagocytosis: Via the EP4 receptor PGE2 signaling suppresses phagocytosis in primary human macrophages. Thus, blockage of COX, e.g. by non-steroidal anti-inflammatory drugs (NSAID), leads to an increase of phagocytosis also in 'inflammatory' M1-like macrophages. This supports the well-described anti-inflammatory effects of these drugs and underscores the importance of the link between the COX branch of the ARA cascade and the regulation of phagocytosis in human macrophages.

Sepsis is a life-threatening multiple organ dysfunction resulting from a dysregulated host response to infection, and patients with sepsis always exhibit a state of immune disorder characterized by both overwhelming inflammation and immunosuppression. The aging of immune system, namely "immunosenescence", has been reported to be correlated with high morbidity and mortality in elderly patients with sepsis. Initially, immunosenescence was considered as a range of age-related alterations in the immune system. However, increasing evidence has proven that persistent inflammation or even a short-term inflammatory challenge during sepsis could trigger accelerated aging of immune cells, which might further exacerbate inflammatory cytokine storm and promote the shift towards immunosuppression. Thus, premature immunosenescence is found in young sepsis individuals, which further aggravates immune disorders and induces the progression of sepsis. Furthermore, in old sepsis patients, the synergistic effects of both sepsis and aging may cause immunosenescence-associated alterations more significantly, resulting in more severe immune dysfunction and a worse prognosis. Therefore, it is necessary to explore the potential therapeutic strategies targeting immunosenescence during sepsis.

KLF15 is involved in cardiovascular disease processes by regulating vascular remodeling and metabolic disorders. Macrophages mediate the inflammatory response in deep vein thrombosis (DVT) by secreting inflammatory cytokines and modulating the fibrinolytic system. Therefore, this study aims to discuss the effect of KLF15 on macrophage polarization in DVT.

In vivo, a DVT animal model was used to assess KLF15 expression and macrophage polarization. In vitro, PMA-treated THP-1 cells with KLF15 overexpression were differentiated into M1- and M2-like macrophages, with polarization markers analyzed by molecular and cellular assays.

In vivo experiments, levels of KLF15, iNOS, CD206, IL-1β, IL-6, IL-10 and TGF-β were increased in the DVT animal model. In vitro experiments, KLF15 overexpression augmented iNOS, CD86, IL-12, TNF-α, IL-1β, and IL-6 levels in M1-like macrophages. Additionally, KLF15 overexpression diminished CD206, IL-10, ARG1, IL-10 and TGF-β levels in M2-like macrophages. In CUT&Tag, peaks bound to KLF15 and lgG were mainly located in the promoter and intronic regions, and KLF15 protein bound more peaks than lgG near the TSS site. YY1, EIF4E, LCK, HMGB1, GPD2, MORF4L1, HIPK2 and NEK2 were hub genes in the peaks that bind to KLF15. ChIP assay confirmed that KLF15 bound the NEK2 promoter in M1-like macrophages and enhanced its transcription and NF-κB pathway activity.

KLF15 facilitates M1 macrophage polarization in DVT via the NEK2/NF-κB pathway, highlighting its potential as a therapeutic target for DVT management. Future studies are warranted to explore its clinical applicability and mechanistic nuances.

The tumor microenvironment (TME) impedes the effectiveness of therapeutic strategies such as chemodynamic therapy (CDT). This study presents a novel nanoscale drug delivery system designed for the precise release of the chemotherapeutic agent doxorubicin (DOX), aiming to overcome treatment limitations, reduce systemic toxicity, and enhance antitumor efficacy. Mn(III) serves as an immunomodulatory agent, while Cu(II) regulates the levels of glutathione (GSH). Layered double hydroxides (LDHs) were synthesized and efficiently loaded with DOX, followed by surface modification with hyaluronic acid (HA). The HA-coated LDH/DOX nanocarriers showed effective internalization by tumor cells and provided a pH-responsive release of DOX. In vitro, the LDH/HA/DOX complex exhibited strong catalytic activity in the Fenton reaction. In vivo studies using an H22 hepatocarcinoma model confirmed its potent antitumor activity and excellent biocompatibility. Immunohistochemical analyses revealed that treatment with LDH/HA/DOX significantly increased infiltration of M1-polarized tumor-associated macrophages (TAMs), CD4 + T cells and CD8 + T cells, while decreasing M2-polarized TAMs. This change in immune cell profile was associated with notable tumor growth inhibition.

The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, and effective treatment is urgently needed. To understand the molecular mechanisms behind the effectiveness of bariatric surgery in treating NASH, we integrated single-cell and bulk RNA sequencing data to identify the role of liver macrophage polarization in alleviating NASH and screen possible drugs for treatment. Analysis revealed that bariatric surgery alleviates NASH by inhibiting liver M1 macrophage polarization with 12 differentially expressed M1 macrophage-related genes. Additionally, 56 potentially effective drugs were predicted for NASH treatment. These findings shed light on the effectiveness of bariatric surgery in treating NASH and offer potential drug candidates for further exploration.

The family with the sequence similarity 198 member B (FAM198B) has been found to contribute to the progression of gastric cancer (GC). However, the role and molecular mechanism of FAM198B in GC remains poorly understood. This work found a link between FAM198B and quercetin, and the regulatory effect of FAM198B on the MAPK pathway of GC.

FAM198B expression was identified through multiple public data sets and verified in clinical tissue samples. The associations between FAM198B and the prognosis of patients with GC were analyzed via the Kaplan‒Meier plotter and Cox regression analysis. Gene set enrichment analysis, coexpressed genes, and RNA sequencing were used to explore the related functions and signaling pathways of FAM198B in GC. In vitro assays assessed the effects of FAM198B knockdown on GC cells. FAM198B was found as a quercetin target by the HERB database and in vitro assays.

FAM198B was highly expressed in tissues from GC patients (p<0.001) and was positively associated with poor prognosis (p<0.001) and immune cell infiltration in GC patients. FAM198B knockdown inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of GC cells (all p<0.05). In addition, FAM198B knockdown decreased the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.01). Quercetin inhibited FAM198B expression and the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.05).

Quercetin inhibits the proliferation, migration, invasion, and EMT of GC cells by inhibiting the FAM198B/MAPK signaling pathway. These discoveries lay the groundwork for developing the treatment of GC by quercetin and targeting FAM198B. In the future, more preclinical and clinical studies are needed to confirm the efficacy and safety of quercetin and target FAM198B in GC.

Thyroid carcinoma, with limited efficacy of current treatment, influences the lives and health of many people. It is important to explore potential therapeutic targets for thyroid carcinoma. Fibromodulin (FMOD) has been indicated to be connected with the progression of different kinds of tumors, with unknown functions in thyroid carcinoma. In this study, the potential candidate therapeutic targets for thyroid carcinoma were identified by bioinformatics methods, and FMOD was screened out for verification. Cell counting kit-8, wound healing, transwell, and flow cytometry assays were conducted to determine the role of FMOD overexpression in cell viability, migration, invasion, and apoptotic rate of thyroid carcinoma cells, respectively. Subcutaneous tumor growth was monitored in nude mice. Tumor-associated macrophages (TAMs) were co-cultured with thyroid carcinoma cells, and the surface marker of M1-like TAMs, CD80, was identified by flow cytometry. Ras-association proximate 1B (Rap1B), the downstream target of FMOD, was predicted by bioinformatic techniques and validated by Rap1B overexpression rescue. FMOD was identified as a tumor suppressor gene in thyroid carcinoma through bioinformatic techniques. FMOD overexpression inhibited cell viability, migration, and invasion and stimulated apoptosis of thyroid carcinoma cells. In vivo, FMOD upregulation could suppress the growth of solid tumors. Moreover, FMOD overexpression in thyroid carcinoma cells promoted M1-like TAM polarization. FMOD downregulated Rap1B expression in thyroid carcinoma cells, and Rap1B overexpression rescue reversed the impact of FMOD on tumor progression and TAM polarization. In conclusion, FMOD exhibited an inhibitory effect on thyroid carcinoma by stimulating M1-like TAM polarization via targeting Rap1B.

Diabetic foot represents a significant healthcare challenge, accounting for a substantial portion of diabetes-related hospitalizations and amputations globally. The complexity of diabetic foot management stems from the interplay of poor glycemic control, neuropathy, and peripheral vascular disease, which hinder wound healing processes. The high incidence, recurrence, and amputation rates associated with diabetic foot underscore the urgency for innovative treatment strategies. Recent advancements in nanotechnology, particularly the emergence of MXenes (two-dimensional transition metal carbides and/or nitrides), have shown promising potential in addressing these challenges by offering unique physicochemical and biological properties suitable for various biomedical applications. It is a novel potential strategy for diabetic foot wound healing in the future. This review comprehensively summarizes current knowledge, unique characteristics, and underlying mechanisms of MXenes in the context of diabetic foot management. Additionally, we propose the potential application of MXenes-based therapeutic strategies in diabetes foot. Furthermore, we also provide an overview of their current challenges and the future perspectives in related fields of diabetic wound healing.

Maltol, primarily derived from Korean red ginseng, exhibits anti-inflammatory properties by modulating macrophage polarization and has potential therapeutic effects on postmenopausal osteoporosis, a condition linked to inflammation. This study explored the molecular mechanisms underlying maltol's ability to inhibit M1 macrophage polarization and regulate osteoblast differentiation via macrophage-mediated pathways. Using in vitro and in vivo models, we demonstrated that maltol upregulates RNF213, which inhibits the CDK14-Pdgfrβ signaling pathway, suppressing M1 polarization and reducing NFκB phosphorylation and pro-inflammatory cytokine production. Additionally, maltol decreases TNFSF12 secretion, mitigating estrogen deficiency-induced osteoblast apoptosis and promoting differentiation. These findings highlight maltol's potential in managing postmenopausal osteoporosis and other inflammatory diseases.

Macrophages play a crucial role in antimicrobial host defense and those with differential maturation/differentiation status differ in inflammatory responses. Herein, GM-CSF and M-CSF primed mouse bone marrow derived macrophages (GM-BMDMs, GM and M-BMDMs, M), the well-established macrophage models in vitro, were utilized and their dynamic signaling changes in response to gram-negative bacteria component LPS treatment were analyzed using both 4D label-free proteomics and phosphoproteomics. Protein changes maintained relatively constant within or across GM and M macrophages post LPS challenge while phospho-protein exhibited more diverse and transient changes. Early induction of phospho-mediated GTPase activities, mRNA processing, and protein-mediated metabolic changes like oxidative phosphorylation (OXPHOS)/mitochondria function was identified at 1 h and maintained until 6 h post LPS treatment in GM and M while canonical TLR mediated MyD88-dependent and -independent pathways were activated at 3 and 6 h, individually at protein levels. Classical and novel phospho-sites for MyD88 and TRIF signaling pathways were also detected by phosphoproteomics. Comprehensively, the integrated protein and phospho-protein trend analysis was conducted and the core protein-phospho-protein network for the early phase actin reorganization, phagocytosis, and TLR signaling in both GM and M were presented. Taken together, these data described differences and similarities between these two types of macrophages in terms of their inflammatory responses to LPS.

Due to poor angiogenesis under the wound bed, wound treatment remains a clinical challenge. Therefore, there is an urgent need for new dressings to combat bacterial infections, accelerate angiogenesis, and accelerate wound healing. In this study, we prepared carbon dots nanomaterial (PF-CDs) derived from traditional Chinese medicine paeoniflorin using a simple green one pot hydrothermal method. The average particle size of the CSs we prepared was 4 nm, and a concentration of 200 μg ml-1was ultimately selected for experiments. Subsequently, PF-CDs were loaded into the chitosan hydrogel to form a new type of wound dressing CSMA@PF-CDs hydrogel. CSMA@PF-CDs demonstrated positive biocompatibility by promoting a 20% increase in cell proliferation and strong antibacterial activity. In comparison to the control group, CSMA@PF-CDs enhanced the expression level of anti-inflammatory factors by at least 2.5 times and reduces the expression level of pro-inflammatory factors by at least 3 times. Furthermore, CSMA@PF-CDs promoted the migration of Human umbilical vein endothelial cells and increased vascular endothelial growth factor expression by 5 times. The results ofin vivoexperiments indicate that CSMA@PF-CDs significantly promoted the healing of back wounds in rats. These characteristics make it a promising material for repairing infected wounds and a potential candidate for clinical skin regeneration applications.

Silicosis, a chronic lung disease, results from prolonged inhalation of silica dust (SiO2) in occupational environments, and its pathogenesis remains incompletely elucidated. Studies have shown that alveolar macrophages (AMs) play a pivotal role in its development. These AMs phagocytose the inhaled SiO2, which leads to morphological, structural, and functional abnormalities that result in lung fibrosis. During this process, adenosine triphosphate (ATP) not only provides energy for the physiological and pathological activities but also acts as a key intracellular and extracellular signaling molecule and regulates cytokine synthesis and secretion. This complex process has not been systematically summarized. In this study, first, the current data on ATP metabolism in the development of SiO2-induced pulmonary fibrosis are introduced. ATP metabolism disorder, caused by impaired production, utilization, or distribution of ATP, disrupts macrophage energy homeostasis. Then, how ATP metabolism disorder affects macrophage morphology and function and the inflammatory and fibrotic processes of the lungs by activating the P2X7 receptor-mediated ATP signaling pathway are discussed. Finally, current therapeutic strategies targeting ATP metabolism disorder and ATP signaling pathways in silicosis are summarized. In conclusion, SiO2-induced ATP metabolism disorder indirectly accelerates the progression of silicosis fibrosis.

Ursolic acid (UA), a prevalent pentacyclic triterpenoid found in numerous fruits and herbs, has garnered significant attention for its vital role in anti-inflammatory processes and immune regulation. The study of immune cells has consistently been a focal point, particularly regarding macrophages, which play crucial roles in antigen presentation, immunomodulation, the inflammatory response, and pathogen phagocytosis. This paper reveals the underlying regulatory effects of UA on the function of macrophages and the specific therapeutic effects of UA on a variety of diseases. Owing to the superior effect of UA on macrophages, different types of macrophages in different tissues have been described. Through the multifaceted regulation of macrophage function, UA may provide new ideas for the development of novel anti-inflammatory and immunomodulatory drugs. However, to facilitate its translation into actual medical means, the specific mechanism of UA in macrophages and its clinical application still need to be further studied.

Lung adenocarcinoma (LUAD) is a major cause of cancer-related mortality worldwide. Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), influencing tumor progression and immune response. Ferroptosis, an iron-dependent form of regulated cell death, has been implicated in tumor biology, but its role within TAMs in LUAD remains unclear.

This study aimed to screen key genes associated with ferroptosis in macrophages and construct a prognostic risk model for LUAD based on these genes.

Integrating the TCGA-LUAD, GSE131907, and GSE13213 datasets, macrophage heterogeneity was analyzed through single-cell dimensionality reduction clustering, pseudotime analysis, and cell-cell communication. Using the GeneCards ferroptosis gene set (1515 genes), ferroptosis-related differentially expressed genes in macrophages were screened. Eight machine learning algorithms (LASSO, SVM, XGBoost, etc.) were leveraged to identify prognostic genes and build a Cox regression risk model. The functional roles of key genes were validated through immune infiltration analysis, drug sensitivity prediction, and Western blot analysis.

Single-cell analysis revealed that macrophages in LUAD lead intercellular communication through the MIF (CD74+CXCR4) ligand-receptor interaction, with ferroptosis-related genes (FRGs) highly expressed in macrophages. 73 macrophage FRGs were identified, and through multi-algorithm cross-validation, HLF, HPCAL1, and NUPR1 were determined as core genes. The risk model (Risk Score = HLF × (-0.153) + HPCAL1 × 0.261 + NUPR1 × (-0.21)) demonstrated robust predictive performance in both the TCGA and GSE13213 cohorts, with 1-, 3-, and 5-year AUC values of 0.756, 0.753, and 0.705. The high-risk group was enriched in tumor progression pathways (like epithelial-mesenchymal transition, cell cycle checkpoints), exhibited low expression of immune checkpoint genes (BTLA, CD47), and showed increased sensitivity to cyclophosphamide and crizotinib. Western blotting confirmed the expression levels of HLF, HPCAL1, and NUPR1 were remarkably lower in LUAD cell lines compared to normal bronchial epithelial cells (P < 0.05).

The research is the first to build a LUAD prognostic model based on macrophage ferroptosis-related genes (HLF, HPCAL1, NUPR1), revealing the immune microenvironment characteristics and drug sensitivity differences in the high-risk group. These findings provide new strategies for precision therapy targeting ferroptosis in tumor-associated macrophages (TAMs).

Inflammatory bowel disease (IBD), a chronic immune disorder, has increasing global incidence and poor treatment outcome. Abnormal macrophage function is implicated in the pathophysiology of IBD. In this study, we investigated the mechanism by which human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) inhibit inflammation in IBD mouse and macrophage inflammation models.

We established a dextran sodium sulfate (DSS)-induce BALB/c mice model of IBD and treated with hucMSC-Ex via tail vein to evaluate their repair effect on IBD mice. An in vitro macrophage inflammation model was established using lipopolysaccharide (LPS) and Nigericin (Nig) by stimulating mouse macrophage RAW264.7 and human myeloid leukemia mononuclear (THP-1) cells to assess the repair effect of hucMSC-Ex on macrophage inflammation. EX 527, an effective inhibitor of silent information regulator of transcription 1 (SIRT1), was employed in both the in vivo and in vitro models to explore the effect of hucMSC-Ex on the SIRT1-FXR (farnesoid X receptor) pathway in macrophages during the attenuation of inflammation.

HucMSC-Ex effectively inhibited inflammation in both the in vivo and in vitro models by up-regulating the expressions of SIRT1 and FXR, which reduced the acetylation level of FXR and inhibited the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome. The addition of EX 527 further proved that hucMSC-Ex can reduce the acetylation of FXR by activating the SIRT1-FXR pathway, and the decrease of FXR acetylation was directly related to the inhibition of the activity of the NLRP3 inflammasome.

HucMSC-Ex alleviates IBD by reducing the acetylation level of FXR through activating the SIRT1-FXR pathway in macrophages and directly negatively regulating the activation of NLRP3 inflammasomes, thus inhibiting the occurrence of the inflammatory process.