People with chronic kidney disease (CKD) often experience poor muscle quality and elevations in skeletal muscle wasting and dysfunction, contributing to a reduced quality of life and an increased risk of morbidity and mortality. The adipokine chemerin is associated with CKD progression and is involved in inflammatory-related signalling processes. With chronic inflammation recognised as a driving factor in uraemic sarcopenia, we aimed to investigate the potential role of chemerin as a uraemic toxin in CKD and identify the mechanisms of action to elucidate therapeutic opportunities in uraemic sarcopenia. To achieve this, we used a holistic approach utilising in-vivo, ex-vivo and in-vitro analyses in order to explore the link between chemerin and skeletal muscle in the context of CKD. Chemerin levels from EDTA-plasma and urine samples were quantified via ELISA on basal samples from those across the kidney disease continuum. Chemerin levels were correlated with eGFR and measures of body composition, physical performance, muscle mass, and muscle quality. A sub-set of participants from each group underwent skeletal muscle biopsies, and samples were processed for gene and protein analysis, or cells extracted for in-vitro experimentation. For in-vitro experiments, human-derived muscle cells (HDMCs) isolated from CKD or aged-matched controls (CON) were differentiated and subsequently exposed to a dose-response of Chemerin. Subsequent experiments used the CMKLR1 selective inhibitor to seek to identify a mechanism of action. Higher circulating chemerin was associated with lower eGFR (R2 = 0.3262, p < 0.001). Positive correlations with body fat % and BMI were noted in CKD patients. Higher circulatory chemerin was associated with poorer muscle quality (R2 = 0.043, p = 0.057). The expression of Chemerin and its proposed receptor of interest CMKLR1 was detected in skeletal muscle. In-vitro analysis showed that the exposure of CKD-derived muscle cells to chemerin induced a significant inflammatory response (IL-6 p < 0.001; CCL-2 p = 0.0215), which was halved using the CMKLR1 receptor inhibitor αNETA (IL-6 p < 0.001; CCL-2 p < 0.001). We report that chemerin is a uraemic toxin in those with CKD and may contribute to poorer muscle quality in these people. Chemerin can moderate indicators of inflammation within HDMCs via the activation of CMKLR1 and warrants further investigations to validate it as a potential new therapeutic target to alleviate the symptoms of uraemic sarcopenia.
Understanding the associations between genetic markers, serological subsets and clinical manifestations in patients with Systemic lupus erythematosus (SLE) may elucidate disease mechanisms and inform personalised treatment strategies. This study aimed to classify SLE patients into distinct subsets based on autoantibody profiles and to examine associations with clinical and genetic characteristics, focusing on key risk loci. A cohort of 846 SLE patients from the Danish SLE Gene-Environment Interaction study (SLE-GEIST) was analysed. Patients were grouped by cluster analysis of cumulative history of autoantibody positivity, and genotyped for known risk alleles, including HLA and non-HLA variants. Multinomial, multivariable logistic regression models were employed to identify associations between autoantibody subsets, clinical manifestations, and genetic markers. Six serological subsets with distinct characteristics were identified. The NCF2 variant was significantly associated with the subset characterised by antiphospholipid antibodies, showing an odds ratio (OR) of 2.42 (95% confidence interval [CI] 1.24-4.74) for co-positivity of anti-cardiolipin IgG and anti-beta2-glycoprotein IgG. This subset also demonstrated a higher prevalence of thrombocytopenia (OR 2.16, 95% CI 1.41-3.29). The DRB3-DQB2 haplotype exhibited a strong association with anti-SSB positivity (OR 4.85, 95% CI 2.57-9.5) and was inversely related to lupus nephritis (OR 0.57, 95% CI 0.34-0.95). This study shows how the clinical and serological complexity of SLE is associated with the genetic diversity of HLA and non-HLA regions. We thus suggest further investigation of mechanistic correlates to variations in the NCF2 gene as well as the tight association between DRB3-DQB2 haplotype and anti-SSB production.
Signal transducer and activator of transcription 3 (STAT3) is activated by various cytokines including interleukin (IL)-6, IL-17, and IL-23, which have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). STAT3 activation plays a key role in the underlying immunological dysregulation. The efficacy of inhibiting the Janus-activated kinase (JAK)/STAT3 pathway in animal models and patients with lupus is known. However, many existing STAT3 inhibitors lack specificity. Here, we aimed to examine the efficacy of two novel small molecules, Huchembio (HCB)-5009 and HCB-5018, which selectively inhibit STAT3 transcriptional activity, in alleviating disease severity. The potential action mechanism of HCB-5009 and HCB-5018, associated with modulation of STAT3-related signaling and inflammatory cytokines, was investigated in MRL/lpr lupus-prone mice. Twenty-one female MRL/lpr mice were administered treatments over 4 weeks, and the expression of key markers of SLE and proteins were evaluated. Luciferase reporter gene assay was used to assess the effects of the test compounds on STAT signaling pathways in various stable cell lines. Mice treated with the HCB molecules exhibited improvements in lupus symptoms, with decreased levels of anti-dsDNA antibodies and inflammatory cytokines and increased levels of C3 complement. Histopathological analysis of the kidney tissue confirmed that the HCB molecules attenuated inflammation in MRL/lpr mice, suggesting that the STAT3 pathway is involved in lupus progression in mice, and that the observed effects are consistent with modulation of STAT3-related pathways. Collectively, these results suggest that HCB molecules exert therapeutic effects in a lupus mouse model, with effects associated with STAT3 pathway modulation, particularly supported by mechanistic observations for HCB-5018. Further studies, including detailed pharmacokinetic and mechanistic analyses, will be required to fully elucidate their mode of action.
Eicosanoids, a diverse family of lipid mediators from arachidonic acid (AA), are fundamental regulators of inflammation and cellular signaling. Concurrently, regulated cell death (RCD) pathways-including apoptosis, necroptosis, pyroptosis, and ferroptosis-are essential, genetically encoded programs that maintain tissue homeostasis by eliminating damaged or unwanted cells. A growing body of evidence reveals that these two systems are not independent but are deeply and mechanistically intertwined, forming a critical axis that dictates cell fate. Through a systematic evaluation of current literature, this review synthesizes the multifaceted nature of this crosstalk. An analysis is presented of the molecular mechanisms by which cyclooxygenase (COX)-derived prostaglandins, such as prostaglandin E₂ (PGE₂), exert a dual influence on apoptosis, promoting survival in cancer while triggering death in immune cells. The temporal regulation of immunogenic cell death (ICD) is further explored, wherein lipoxygenase (LOX)-derived leukotrienes amplify lytic death pathways, while specialized pro-resolving mediators (SPMs) suppress them to restore homeostasis. A central focus is the paradigm-shifting discovery of LOX enzymes as direct executioners of ferroptosis, an iron-dependent form of RCD driven by catastrophic lipid peroxidation. Crucially, this review expands upon previously overlooked intracellular mediators, explicitly detailing how eicosanoid-driven oxidative stress and mitochondrial dysfunction act as fundamental convergence points for RCD modulation. Furthermore, emerging RCD modalities such as PANoptosis and cuproptosis are discussed to highlight the expanding landscape of this crosstalk. Dysregulation of this eicosanoid-RCD axis is a key driver in pathologies ranging from cancer and chronic autoimmunity to neurodegenerative diseases and cardiovascular disorders. By systematizing these molecular touchpoints, this review highlights emerging therapeutic strategies aimed at precisely targeting this nexus to restore homeostasis and treat human disease.
The global incidence rate of Crohn's disease (CD) is rising, with mesenteric adipose tissue (MAT) playing a pivotal role in CD progression, particularly in fibrosis development. This study aimed to identify key genes in MAT that contribute to CD progression, thereby providing insights for potential therapeutic strategies. The CD-related datasets from the GEO database were aggregated to analyze differentially expressed secreted protein genes. Colon tissue and MAT were harvested from CD subjects and healthy subjects, and H&E and Masson staining were used to detect pathological changes. The expression level of the target gene was determined using various methods (including qRT-PCR, IHC, IF, and Western blot). Primary mesenteric adipocytes of CD patients and healthy controls were isolated and cultured, and epiregulin (EREG) expression was intervened to explore its effects on inflammatory cytokine secretion and lipid metabolism. Additionally, an in-vitro co-culture system of primary adipocytes and intestinal epithelial cells (IECs) and an in-vivo 2,4,6-Trinitrobenzene sulfonic acid (TNBS)-induced CD rat model were constructed to explore the effect of EREG on CD symptoms and the underlying mechanisms. EREG was highly expressed in both CD colon tissues and MAT. Overexpression of EREG in adipocytes facilitated the production of inflammatory factors and lipid metabolism, as well as promoted inflammation and fibrosis in co-cultured IECs. In vivo, EREG knockdown effectively alleviated CD symptoms and fibrosis in TNBS-induced CD rats. The underlying mechanism may be mediated by EREG, promoting epithelial-mesenchymal transition (EMT) and the PPARγ signaling pathways in IECs. Inflammatory cytokines TNF-α and IL-17A induced EREG expression in adipocytes from CD patients CONCLUSION: The abnormal upregulation of EREG in adipocytes within MAT contributes to the pathogenesis of CD by promoting inflammation and fibrosis. Targeting EREG may offer a novel therapeutic approach for the clinical treatment of CD.
Bone remodelling is a dynamic process of osteoblastic bone formation and osteoclastic bone resorption, regulated by local, paracrine and endocrine factors, in which osteocytes act as orchestrators of bone homeostasis. Among these regulatory factors, the neuropeptide VIP (vasoactive intestinal peptide) has demonstrated osteoprotective effects by inhibiting osteoclastogenesis and promoting osteoblast differentiation. However, its potential role in osteocyte biology remains unexplored. In this study, we investigated the effect of VIP on the differentiation of primary human osteocytes. We describe for the first time the expression of VIP and its receptors during in vitro osteocyte differentiation. Our results show that VIP promotes osteocytogenesis, accompanied by a reduction in the RANKL/OPG ratio, thereby supporting its role as an anti-osteoclastogenic factor. To better mimic the complexity of bone tissue, we performed triple co-cultures of osteoblasts and simultaneously differentiating osteocytes and osteoclasts, in the presence or absence of VIP. Our results confirmed that VIP supports the osteoblast-to-osteocyte transition and promotes an osteoprotective phenotype, characterized by a reduced RANKL/OPG ratio and decreased SOST expression. The downregulation of sclerostin may attenuate osteocyte-mediated inhibitory signalling toward osteoblasts and, in turn, contribute to the reduction of the osteoblastic RANKL/OPG ratio. Collectively, our findings reinforce the anti-osteoclastogenic actions of VIP, supporting its role as a potential osteoprotective factor.
Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by loss of dystrophin, and characterized by progressive muscle wasting, with massive replacement of muscle fibers with adipose tissue. Yet, the early molecular events that initiate pathology remain poorly defined. Here, we combined longitudinal RNA sequencing of sapje dystrophic zebrafish (a single-mutation vertebrate model of human DMD characterized by a severe phenotype), transcriptomic profiling of human DMD myoblasts and myotubes, and functional in vivo imaging using pathway-specific zebrafish biosensors to reconstruct the cascade of events triggered by dystrophin deficiency. We observed that the earliest stages of disease are characterized by marked downregulation of genes controlling cytosolic Ca2+ homeostasis, mitochondrial function and organization, and Pax3/Mef2a/Srf-mediated transcriptional programs essential for satellite cell maintenance and muscle differentiation. These early deficits precede robust but ineffective regenerative and metabolic compensatory responses, accompanied by extracellular matrix remodeling and TGFβ activation. At advanced stages, both sapje zebrafish and human DMD myotubes converge on profound mitochondrial dysfunction, impaired cell-cycle control, and chronic inflammation signaling. Live imaging of sapje zebrafish biosensors validated these transcriptomic signatures, revealing reduced Notch, Bmp, Shh, Hif-1a and Wnt signaling, along with aberrant TGFβ activity and disrupted mitochondrial dynamics in vivo. Together, these findings identify a conserved temporal sequence linking early Ca2+ dysregulation to mitochondrial failure, satellite cell hyperactivation, and fibrotic remodeling, providing mechanistic insights and therapeutic targets for early intervention in DMD patients.
Sepsis is a complicated clinical disease caused by an infection-related host response, which results in acute organ dysfunction and a high mortality risk. Among the affected organs, the lungs are particularly susceptible to sepsis. Sepsis-induced acute lung injury (SI-ALI) is a common and severe complication observed among septic patients. Neutrophil extracellular traps (NETs) serve a significant role in immune and inflammatory regulation. Our previous studies have shown a close association between NETs and SI-ALI. However, the mechanism by which NETs mediate the interaction between endothelial cell (EC) barrier integrity and inflammatory responses remains incompletely understood. By reanalyzing our RNA-seq data, we discovered that NET-stimulated HUVECs had an increased cell adhesion molecules pathway, and the differentially expressed genes Wnt7a, HDAC5, and Claudin-5 were screened out. The relationships between differentially expressed genes were further established by STRING analysis. The expression levels of Claudin-5 and Wnt7a/β-catenin/HDAC5 signaling pathway proteins were evaluated by quantitative PCR (qPCR), western blotting, and immunofluorescence staining. At the same time, a cecal ligation and puncture (CLP) model was used to induce sepsis in mice to investigate the function of NETs in vivo. In our research, we demonstrated that NETs activate HDAC5 gene expression through the Wnt7a/β-catenin signaling activation, which subsequently downregulated the expression of tight junction (TJ) proteins, including Claudin-5, ZO-1, and Occludin. This led to impaired barrier function in lung microvascular endothelial cells and worsened the prognosis in a murine model of SI-ALI. Moreover, the NETs disruption and Wnt7a or HDAC5 inhibition mitigated the degradation of tight junction proteins in endothelial cells and improved outcomes in septic mice. In conclusion, our findings indicate that NETs contribute to lung endothelial barrier dysfunction via the Wnt7a/β-catenin/HDAC5 axis during the progression of SI-ALI.
Immune checkpoint inhibitors are widely used in non-small cell lung cancer (NSCLC), but with limited overall response rates. Indicators predicting immunotherapy response are hard to routinely detect due to their invasiveness. This study systematically screened for CD8+T-cell epitopes in Cytokeratin Fragment Antigen 21-1 (Cyfra21-1), a valuable NSCLC tumor marker, through a combination of in silico prediction, ex vivo co-cultures of peptides with patient-derived peripheral blood mononuclear cells (PBMCs), peptide competition binding assays, and peptide immunization in humanized mice. A total of 37 novel CD8+T-cell epitopes were confirmed to exhibit immunogenicity in a real-world lung cancer cohort comprising 150 patients. These epitopes were restricted by 13 HLA-A, 15 HLA-B, and 14 HLA-C prevalent allotypes which cover the majority of Northeast Asian population. Using these epitope peptides, a universal ELISpot assay was established to count reactive Cyfra21-1-specific CD8+T cells, and a cohort of 70 NSCLC patients scheduled to receive PD-1/PD-L1 inhibitor therapy was tested. The baseline count of reactive Cyfra21-1-specific CD8+T cells in PBMCs was identified as an independent predictor of patient responsiveness to immunotherapy, with an AUC of 0.757 and a cut-off value of 25.5 SFUs/4 × 10⁵ PBMCs that distinguished responders from non-responders. This study is the first to construct a broad-spectrum CD8+T-cell epitope library of the Cyfra21-1 antigen in Northeast Asians, establish a universal assay for measuring Cyfra21-1-specific CD8+T cell reactivity, and validate the predictive value of Cyfra21-1-specific CD8+T cells for immunotherapy response in NSCLC patients.
Takotsubo syndrome (TTS) is a stress-induced cardiac disorder that closely resembles acute coronary syndrome but lacks effective and safe therapeutic interventions. This study aimed to investigate the cardioprotective effects of transcutaneous auricular vagus nerve stimulation (taVNS), a noninvasive neuromodulation technique, in a rat model of TTS-like cardiomyopathy. Sprague-Dawley rats were randomly assigned to three groups: sham, TTS, and TTS + taVNS. TTS was induced by intraperitoneal injection of isoprenaline, while taVNS was applied for 1 hour. Cardiac function was assessed using electrocardiography, heart rate variability, and ventricular electrophysiological recordings. Histopathological changes, inflammatory responses, and autonomic nervous system activity were analyzed. RNA sequencing was performed to explore underlying molecular mechanisms, with key findings validated by RT-qPCR and Western blotting. Noninvasive taVNS significantly improved left ventricular dysfunction in TTS rats, reducing arrhythmia susceptibility, myocardial injury, and collagen reaction. The treatment significantly suppressed sympathetic overactivation and systemic inflammation. Transcriptomic analysis identified the TLR2/MAPK pathway as a key mediator of inflammation in taVNS-induced protection. Moreover, taVNS significantly downregulated expression of TLR2/MAPK pathway and proinflammatory cytokines confirmed at both mRNA and protein levels compared to the TTS group. Noninvasive taVNS offers broad cardioprotection in TTS through inhibiting the sympathetic nerve and inflammation. This approach holds promise as an adjunct therapy for TTS, offering benefits in inflammation control, structural preservation, and electrical stability of the heart.
The advent of tissue engineering has revolutionized the development of organs and tissues, enabling the creation of three-dimensional structures that support cell proliferation and differentiation. This process, essential for organ transplantation, ensures biocompatibility, immunogenicity, and structural fidelity by preserving the extracellular matrix and its components, such as growth factors and signaling molecules. In the context of ovarian tissue engineering, the restoration of ovarian function presents a promising avenue for addressing conditions like ovarian insufficiency, which arises from hormonal, genetic, autoimmune factors, or treatments like chemotherapy. Current challenges in ovarian transplantation, including the need for revascularization, highlight the limitations of existing techniques such as oocyte preservation. Tissue engineering approaches, particularly ovarian recellularization through decellularization, show promise in restoring both reproductive and endocrine functions by mimicking the ovarian microenvironment. Emerging technologies, such as 3D printing and CRISPR/Cas9 gene editing, although facing their own limitations, offer complementary methods to enhance ovarian tissue engineering. This review examines the state of the art in artificial ovarian reconstruction, with a focus on restoring endocrine and reproductive functions, ultimately advancing women's health by developing bioengineered ovaries.
Paracoccidioidomycosis (PCM) is a systemic fungal infection endemic in the Americas, with the highest incidence in Brazil. Current treatment relies on antifungal agents such as amphotericin B (AmB), itraconazole, and fluconazole. However, long-term therapy frequently leads to treatment discontinuation and/or sequelae due to drug toxicity, chronic inflammation, and fibrosis, which can severely impair organ function and quality of life. Accordingly, immunomodulatory therapies have emerged, including the use of monoclonal antibodies against the checkpoint molecule CTLA-4. Previously, we demonstrated that CTLA-4 blockade reduced fungal burden, decreased lung lesion severity, and increased survival by enhancing protective immune responses. Therefore, this study aimed to evaluate a combined therapy of anti-CTLA-4 and amphotericin B. C57BL/6 mice were inoculated intratracheally with 1 × 10⁶ Paracoccidioides brasiliensis yeast cells and, after 6 weeks of infection, treated with anti-CTLA-4 and/or AmB. Two weeks after treatment, disease progression was evaluated by CFU counts, histopathology, and survival analysis. Immune responses were assessed by ELISA and flow cytometry. The combined anti-CTLA-4 + AmB therapy resulted in improved disease control, evidenced by reduced fungal burden in the lungs, liver, and spleen, decreased pulmonary tissue damage, and increased survival compared to monotherapies. Additionally, reduced infiltration of dendritic cells and neutrophils, lower expression of activation markers CD80 and CD86, and fewer CD4⁺ T cells in the lungs suggest controlled disease due to diminished antigenic stimulation. These findings demonstrate that CTLA-4-mediated immune modulation and the antifungal activity of amphotericin B act complementarity to control murine PCM, supporting combined therapy as superior to monotherapy.
Intervertebral disc degeneration (IDD), a condition characterized by extracellular matrix (ECM) degradation and nucleus pulposus (NP) cell senescence, compromises disc function. The Akt signaling pathway is essential for NP cell viability and ECM homeostasis. This study identifies the serine/threonine kinase PIM3 as significantly downregulated in degenerated human NP tissues. Notably, PIM3 mRNA expression levels were found to be negatively correlated with the clinical severity of IDD (Pfirrmann grade). The functional role of PIM3 was investigated through knockdown and overexpression experiments in human NP cells. PIM3 overexpression restored cell viability, suppressed senescence, and enhanced ECM protein levels in degenerated NP cells, while its knockdown in normal cells produced the opposite results. These protective effects were critically dependent on the kinase activity of PIM3. Mechanistically, PIM3 was found to physically interact with and activate the Akt signaling pathway, thereby regulating downstream molecules, including mTOR and FoxO1, to modulate cell viability and senescence. In an IDD rat model, AAV-mediated PIM3 overexpression improved ECM integrity, reduced senescence and activated the Akt pathway, mitigating disc degeneration. In conclusion, this study establishes PIM3 as a key regulator of NP cell homeostasis that acts through direct engagement with the Akt/mTOR/FoxO1 axis. Its correlation with disease severity and the kinase-dependent nature of its function highlight PIM3 as a promising, mechanistically-defined therapeutic target for treating IDD.
Myocardial ischemia-reperfusion injury (MI/RI) is a key cause of cardiac dysfunction in patients with acute myocardial infarction after revascularization, with inflammatory imbalance as the core mediating mechanism. Tumor necrosis factor-α-stimulated gene 6 (TSG-6) exerts both anti-inflammatory and pro-inflammatory effects, yet its specific function and molecular mechanism in MI/RI remain unclear. Mouse models with TSG-6-/-and AAV9-mediated overexpression were constructed, and MI/RI and permanent coronary artery ligation models were established in combination with an in vitro macrophage model. Multiple techniques were used to detect myocardial infarct size, cardiac function, molecular expression and cellular function. With the help of NF-κB inhibitors, reactive oxygen species scavengers and Nlrp3 knockout models, the molecular pathway by which TSG-6 regulates MI/RI was explored. Myocardial TSG-6 in mice was upregulated in a time-dependent manner after MI/RI. Knockout TSG-6 alleviated myocardial injury, improved cardiac function and survival rate in mice, whereas overexpression aggravated myocardial infarction and heart failure. In vitro experiments, TSG-6 activated the macrophage NLRP3 inflammasome in a time- and concentration-dependent manner: it activated the priming signal through the NF-κB/P65 pathway and induced mitochondrial oxidative stress damage to promote its activation. Meanwhile, TSG-6 promoted macrophage polarization toward the M1 phenotype via a NLRP3-dependent mechanism, and NLRP3 knockout reversed this effect. TSG-6 exerts pro-inflammatory and pro-injurious effects in MI/RI. Through the dual signals of activating the NF-κB pathway and inducing mitochondrial damage, it promotes the activation of the NLRP3 inflammasome and M1 polarization of macrophages, thereby exacerbating MI/RI. This study clarified the function and mechanism of TSG-6 in regulating MI/RI, laying a theoretical foundation for targeted therapy of myocardial protection.
Cancer-associated fibroblasts (CAFs), representing the predominant stromal cell population within the solid tumor microenvironment (TME), are thought to play a significant role in facilitating tumorigenesis and progression. Nonetheless, recent experimental efforts to eradicate CAFs in solid tumors have inadvertently resulted in tumor progression, potentially due to the tumor-suppressive effects exhibited by specific CAF subtypes. Therefore, strategies that selectively target pro-tumorigenic CAFs may yield more favorable outcomes. Emerging evidence indicates that CAFs are instrumental in reprogramming lipid metabolism within TME, fostering a high-fat, immunosuppressive environment. To adapt to the hypoxic and nutrient-limited conditions of TME, cancer cells alter their metabolic processes, which subsequently influences the behavior of CAFs. The variability among CAF populations affects the metabolic pathways of cancer cells and neighboring immune cells. Despite the importance of these interactions, the discussion regarding lipid metabolism crosstalk between CAFs and the TME remains insufficiently explored in the literature. As a result, this study systematically reviews the various origins and heterogeneity of CAFs and closely investigates their roles in lipid metabolism reprogramming within the TME. Additionally, we analyze the metabolic interactions between CAFs and different components of the TME in solid tumors. Ultimately, we discuss potential therapeutic strategies and the challenges of targeting CAF lipid metabolism.
Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a transformative modality in cancer immunotherapy. While global efforts have advanced the field, China has played a pivotal role in shaping the development and clinical deployment of CAR-T technologies. We, herein, provide a comprehensive evaluation of China's contributions in structural refinements, the antigen-binding domain and intracellular signaling modules of CAR. Moreover, Chinese preclinical studies have addressed on enhancing T cell infiltration, overcoming immune checkpoint resistance, and remodeling the tumor microenvironment. We, further, review the discovery of novel targets, strategies to minimize on-target/off-tumor toxicity, and innovative manufacturing approaches that have optimized product quality and reduced costs. Clinical translation efforts in China have accelerated rapidly, supported by a robust research infrastructure and regulatory framework, leading to a growing portfolio of CAR-T cell products in trials and practice. Future research should focus on enhancing CAR-T cell efficacy against solid tumors, integrating gene editing technologies, and expanding allogeneic platforms for scalable, off-the-shelf therapies.
Mitochondria are fundamental organelles that regulate cellular homeostasis through energy production, metabolic integration, and signaling cascades. Beyond their bioenergetic role, mitochondrial dysfunction is increasingly recognized as a pivotal instigator of PANoptosis, a novel, coordinated inflammatory cell death pathway that amalgamates key features of pyroptosis, apoptosis, and necroptosis. This integrated cell death is executed by multiprotein complexes termed PANoptosomes, which are nucleated by specific sensors like ZBP1, AIM2, and NLRC5. Central to this process is the release of mitochondrial danger signals, including reactive oxygen species (ROS) and mitochondrial DNA (mtDNA), which act as potent upstream triggers. For instance, ROS can directly oxidize and activate necroptotic mediators like RIPK1, while cytosolic mtDNA engages innate immune sensors such as cGAS-STING and inflammasomes, thereby initiating PANoptosome assembly. Concurrently, defects in core mitochondrial processes including impaired oxidative phosphorylation, disrupted dynamics (fission/fusion), and faulty mitophagy exacerbate these inflammatory signals, creating a permissive environment for PANoptosis. This mitochondrial-PANoptosis axis is implicated in the pathogenesis of a broad spectrum of diseases. Consequently, therapeutic strategies targeting mitochondrial integrity or specific PANoptotic components hold significant promise for mitigating pathological inflammation and cell loss. This review focuses on the molecular mechanisms linking mitochondrial dysfunction to PANoptosis and explores the translational potential of this interplay to reshape therapeutic approaches in diseases.
Acute lung injury (ALI), especially when resulting from trauma-associated hemorrhagic shock (THS), is a life-threatening condition with limited treatment options and high mortality. Understanding the molecular mechanisms driving ALI in this context is essential to identify reliable biomarkers and therapeutic targets. This study aimed to explore the transcriptomic alterations and protein interaction networks in a rat model of THS-induced ALI using RNA sequencing and bioinformatics tools. RNA-seq analysis was performed on lung tissues from five THS-induced and five normal rats. Analysis revealed 1003 differentially expressed genes, including 365 upregulated and 638 downregulated. Functional enrichment pointed to significant involvement of pathways related to oxidative stress, hypoxia response, neutrophil degranulation, ferroptosis, and immune activation. Protein-protein interaction network analysis identified four key gene modules, with Module 3 notably associated with iron metabolism and neutrophilic inflammation. Hub genes such as Cd163, Nqo1, Gclc, Lcn2, and Mmp8 were identified as central regulators and validated in independent samples (three THS-induced and three controls). Lcn2 and cathepsins (CTSS, CTSK, CTSL) emerged as particularly relevant for their multifaceted roles in inflammation, iron homeostasis, and matrix remodeling. These findings provide novel insights into the immunometabolic dysregulation underlying THS-induced ALI and suggest promising molecular targets for future therapeutic interventions aimed at mitigating lung injury in critically injured trauma patients.
Atherosclerosis, a chronic inflammatory disease, presents significant "residual risk" even with effective lipid-lowering therapies, primarily due to persistent vascular inflammation. Apolipoprotein B100 (ApoB100) acquires pro-inflammatory properties upon modification and binds to cell-surface enolase 1 (ENO1), an immune modulator upregulated in inflammatory conditions. This interaction induces inflammatory responses via NF-κB activation. Targeting the ApoB100-ENO1 interaction may offer a novel strategy to reduce vascular inflammation and atherosclerosis progression. We developed PP3m, a stabilized ApoB100-derived peptide, to selectively inhibit the ApoB100-ENO1 interaction. Single-cell RNA sequencing (scRNA-seq) data from human atherosclerotic plaques were reanalyzed to characterize ENO1 expression in myeloid cells. In vitro, PP3m's anti-inflammatory effects were evaluated across various macrophage models stimulated by diverse inflammatory stimuli. Outcomes included cytokine secretion, inflammatory gene expression, foam cell formation, oxidized low-density lipoprotein (oxLDL) uptake, and signaling pathways activation. In vivo, Ldlr-/- mice fed an atherogenic diet were treated with PP3m to evaluate its effects on atherosclerosis progression, macrophage accumulation, and systemic inflammation. scRNA-seq analysis revealed that human atherosclerotic plaques harbor significantly more ENO1 macrophages, with ENO1 expression enriched in CD68+ M1 macrophages. Atherogenic stimuli induced ENO1 translocation to the plasma membrane in macrophages. In vitro, PP3m significantly attenuated inflammatory responses by suppressing IL-6 and CXCL8 secretion, reducing M1 polarization, and dose-dependently inhibiting oxLDL-induced foam cell formation and uptake. In vivo, PP3m reduced aortic lesion area, lipid content, and collagen deposition, accompanied by decreased macrophage accumulation in plaques and lower circulating pro-inflammatory cytokines. Importantly, these effects were independent of changes in plasma lipid profiles. The ApoB100-ENO1 axis is a critical driver of macrophage-mediated inflammation in atherosclerosis. The novel peptide PP3m effectively inhibits this interaction, reducing vascular inflammation and plaque progression without altering lipid levels. PP3m represents a promising therapeutic candidate for cardiovascular disease by targeting residual inflammatory risk through a lipid-independent mechanism.
Asthma is a highly heterogeneous chronic inflammatory airway disease with a complex pathophysiology involving interactions among genetic, environmental, and immune factors. Macrophages are the most abundant innate immune cells in the lungs, and their polarization states play a central role in the initiation, persistence, and resolution of asthmatic airway inflammation. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA regulation, serve as a critical bridge connecting environmental stimuli to gene expression. They can influence the course of airway inflammation by modulating the function of immune cells such as macrophages. These distinct epigenetic mechanisms intersect and act synergistically, collectively forming an epigenetic regulatory network that governs macrophage polarization during the pathogenesis of asthma. As increasing attention is focused on the role of epigenetics in asthmatic airway inflammation, identifying epigenetic markers that regulate macrophage polarization and targeting the underlying epigenetic mechanisms of this polarization may provide novel therapeutic strategies for specific asthma endotypes. This review systematically elaborates on the epigenetic mechanisms and the phenomenon of macrophage polarization involved in asthmatic airway inflammation. It further untangles the close relationship between epigenetic mechanisms and macrophage polarization, revealing their key roles in asthmatic airway inflammation and providing a new theoretical basis for asthma treatment strategies.