Cancer is a significant challenge to society and public health in the 21st century. According to GLOBOCAN 2020, there were 19.3 million new cancer cases with approximately 10.0 million deaths in 2020 globally. By 2040, 28 million new cases and 16.2 million deaths are estimated. With the escalating challenges of cancer and limitations of conventional therapies like surgery, chemotherapy, and radiotherapy, the development of novel therapies such as immunotherapy and targeted therapy is required. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has become a significant advancement in cancer treatment, combating tumors by activating the immune system. This review offers a thorough overview of ICIs, including their classification, mechanisms of action, and adverse events. It also examines the application of ICIs across various cancer types especially on advanced or unresectable malignancies, such as head and neck squamous cell carcinoma, esophageal cancer, non-small cell lung cancer, breast cancer, hepatocellular carcinoma, and bladder cancer, highlighting their therapeutic potential and the challenges they face. By providing a comprehensive analysis, this review aims to construct a reference system for clinicians to better understand and utilize ICIs in treating cancer.

This research endeavored to ascertain whether four cycles of oxaliplatin in conjunction with standard radiation (oxaliplatin-CRT) could enhance overall survival when compared with standard neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). A Phase III randomized trial (SONCAR Trial, NCT02031939) was conducted in China, involving patients diagnosed with clinical T3-4 and/or N+ rectal cancer. Patients were randomly allocated to the experimental arm (receiving pelvic radiation (50 Gy/25 fractions) in conjunction with oxaliplatin and capecitabine) or the control arm (pelvic radiation in conjunction with capecitabine alone). The main endpoint was a 5-year OS, while the secondary objectives encompassed pathological complete response (pCR), 3-year disease-free survival, and surgical complications. A total of 536 patients were assessable. The rate of pCR was notably higher in the experimental group (31.9%) than in the control group (21.5%) (p = 0.008). The clinical complete response (cCR) rate was also higher in the experimental group (p = 0.024). Among patients with tumors located within 5 cm of the anal verge, the experimental group exhibited a significantly greater tumor regression, with rates of 33.8% compared to 21.6% in the control group (p = 0.024). In summary, oxaliplatin-CRT significantly augmented the tumor response in LARC patients with manageable toxicity.

Previous studies have shown that the effectiveness of immune checkpoint blockade in the treatment of ovarian cancer (OC) is poor. A promising small molecule inhibitor targeting phosphatidylinositol 3-kinase gamma (PI3Kγ) has recently been applied in combination with other drugs for tumor treatment. This study aimed to determine whether a PI3Kγ inhibitor can enhance the antitumor effects of anti-programmed death-1/programmed death ligand-1 (anti-PD-1/PD-L1) therapies in OC and to explore the underlying immunomolecular mechanism involved. Changes in the expression of PI3Kγ, PD-1, PD-L1, and tumor-associated macrophages (TAMs) during the progression of OC were detected in clinical tissue samples. We also constructed a coculture system of OC cells with lymphocytes for in vitro study, and a subcutaneous and intraperitoneal implantation OC mouse model was constructed for in vivo studies. OC is an immunosuppressed tumor with predominant infiltration of M2 throughout the entire disease course. We also found that a PI3Kγ inhibitor combined with anti-PD-1 therapy can enhance the antitumor effects of anti-PD-1 agents by modulating the PI3Kγ-AKT-NF-κB pathway, reprogramming TAMs, decreasing the number of myeloid-derived suppressor cells, increasing the number of CD8⁺ T cells, and increasing the levels of proinflammatory factors; consequently, this approach transforms the tumor immune microenvironment of OC into a more active state.

Mitochondria are involved in cell survival and metabolic processes including adenosine triphosphate production, heme biosynthesis, reactive oxygen species, and iron and calcium homeostasis. Although mitochondria are well known to contribute to apoptosis, a growing body of evidence indicates that mitochondria modulate nonapoptotic cell death (NACD) mechanisms, including autophagy, necroptosis, ferroptosis, paraptosis, pyroptosis, parthanatosis, and cuproptosis. These NACD pathways differ in molecular triggers, morphological characteristics, and immunological consequences, but they all involve mitochondria. For example, mitochondrial ROS and lipid peroxidation play a role in ferroptosis, whereas mitochondrial depolarization and the release of apoptosis inducing factor are paramount to parthanatosis. Mitochondrial swelling is a hallmark of paraptosis, whereas mitochondrial disruption is associated with pyroptosis. Autophagy, though primarily a survival mechanism, is also regulated by mitochondrial dynamics in cancer cells. In cuproptosis, mitochondrial protein aggregates when iron–sulfur cluster proteins are disrupted, resulting in copper-dependent cell death. There are many factors that influence NACD, including mitochondrial membrane potential, bioenergetics, calcium flux, metabolites, and interactions with the endoplasmic reticulum. The review comprehensively summarizes our understanding of mitochondrial and NACD interactions, particularly in cells resistant to classical apoptosis agents. Therapeutic vulnerabilities associated with mitochondria-mediated NACD could lead to next-generation therapies.

Epilepsy is one of the most common neurological disorders, characterized by the enhancement of neural excitability from a neurocentric perspective. Emerging evidence indicates that microglia play a pivotal role in the pathogenesis of epilepsy through complex and various mechanisms that is still not fully understood. In this study, we demonstrate that the deficiency of transient receptor potential melastatin 2 (TRPM2) channel, a calcium-permeable nonselective cation channel, significantly accelerates seizure development in multiple mouse seizure models, including MES- and pentylenetetrazole(PTZ)-induced seizure model, intrahippocampal KA model, hippocampal kindling model, without affecting seizure susceptibility in initial acute seizure. Notably, it is the deficiency of TRPM2 specifically in microglia, rather than in CaMKIIα⁺ excitatory neurons or PV⁺ interneurons, that primarily responsible for seizure development. Moreover, microglial TRPM2 deficiency increases the excitability of hippocampal pyramidal neurons by enhancing the AMPAR-mediated excitatory synaptic transmission independent of changes in the expression of inflammatory cytokines. These findings reveal a previously unrecognized, inflammation-independent mechanism by which microglial instead of neuronal TRPM2 channel contributes to seizure development, highlighting microglial TRPM2 as a novel potential therapeutic target for epilepsy by specifically targeting microglial TRPM2 channel.

The clinical success of PD-1/PD-L1 blockade has revolutionized cancer immunotherapy. However, the issues of immune resistance have become increasingly prominent, representing a critical limitation in modern oncology. This phenomenon has prompted efforts to elucidate the mechanisms underlying both types of resistance and to find breakthrough therapeutic strategies. This article provides a comprehensive overview of PD-1/PD-L1 blockade resistance mechanisms from both primary and acquired resistance perspectives, including tumor intrinsic factors, immune microenvironment components, and systemic factors. Building on this foundation, emerging research demonstrates that type I interferons (IFNs), particularly IFN-α and IFN-β, play crucial immunomodulatory roles in overcoming resistance to PD-1/PD-L1 blockade. We delineate six molecular mechanisms through which IFN-α/β enhance PD-1/PD-L1 blockade efficacy, and innovative strategies are proposed to therapeutically boost IFN-α/β production, including gene editing techniques, targeting the cGAS-STING or TLR pathway and so on. Furthermore, insights into current challenges and future directions of the application of IFN-α/β to improve PD-1/PD-L1 blockade are discussed. This review holds significant academic value by not only synthesizing current knowledge on PD-1/PD-L1 resistance mechanisms but also pioneering a framework for leveraging type I IFNs to overcome these barriers.

Obesity and aging are major risk factors for diseases such as Type 2 diabetes mellitus, dementia, and osteoporosis. High-fat diet (HFD) consumption is one of the most important factors contributing to obesity. To elucidate and provide resources on how long-term HFD to aging (LHA) affects the bone marrow and solid organs, we established an LHA mice model and demonstrated that LHA caused a shift from osteogenesis to adipogenesis in the bone marrow microenvironment. Single-cell transcriptomics of bone marrow cells highlighted LHA-driven perturbations in immune cell populations with distinct metabolic adaptations to LHA. We demonstrated that bone marrow macrophages of the LHA group upregulated Chil3 and Fabp4, which are associated with inflammatory response and regulation of adipocytes. Moreover, we identified the Ptn–Sdc3 axis and Cxcl12–Cxcr4 axis between bone marrow macrophages and brain epithelial cells as possible candidates for crosstalk between bone marrow and brain in LHA mice. Our findings indicated the bone marrow microenvironment as a central hub of LHA-induced pathology, where adipogenic reprogramming and myeloid cell dysfunction collectively drive skeletal and systematic inflammation. This resource highlights therapeutic opportunities targeting bone marrow to mitigate obesity-accelerated aging.

Extracellular matrix (ECM) is a dynamic, three-dimensional network that provides structural support and regulates key biological processes, including cell adhesion, migration, differentiation, and signal transduction. Its mechanical properties, such as stiffness, topology, and viscoelasticity, are crucial in normal and pathological conditions, influencing cell behavior through mechanotransduction pathways. Dysregulation of ECM is linked to various diseases, making a thorough understanding of its composition and properties essential. This review discusses ECM composition, physical properties, and the limitations of in vitro ECM models. It highlights the role of ECM in tissue homeostasis, particularly in regulating cell behavior via mechanotransduction, focusing on force-sensitive sensors like integrins, Piezo1, TRPV4, and YAP/TAZ. Additionally, the review explores ECM remodeling in cancer, fibrosis, and cardiovascular diseases, along with current therapeutic strategies targeting ECM components, such as nanotechnology-based therapies, small molecule inhibitors, and CAF-targeted therapies. Challenges and clinical applications of these therapies are also discussed. Finally, the review looks ahead to future research, emphasizing the integration of ECM-targeted therapies in precision medicine and novel approaches to normalizing ECM composition and structure for therapeutic benefits. This review provides mechanobiological insights into therapeutic strategies targeting the ECM.

Lactate is a vital metabolite in cancer, significantly impacting tumor progression, metastasis, and overall survival. The CD147–monocarboxylate transporter 1 (MCT1) complex, a major lactate transporter, has emerged as a promising therapeutic target. However, no effective protein–protein interaction (PPI) inhibitors targeting the CD147–MCT1 complex have been identified. In this study, we found that the small-molecule inhibitor crizotinib effectively disrupts the CD147–MCT1 interaction, leading to reduced lactate secretion from melanoma cells and decreased lactate uptake by macrophages. In vivo studies demonstrated that crizotinib treatment significantly suppressed tumor growth and enhanced responsiveness to immune checkpoint blockade therapy. Flow cytometry revealed that this metabolic intervention inhibits M2 polarization and reshapes the tumor immune microenvironment. Transcriptomic analysis further revealed that lactate induces C-X-C motif chemokine ligand 13 (CXCL13) expression in macrophages, which enhances melanoma invasiveness and impairs immune cell-mediated cytotoxicity. Importantly, crizotinib suppresses CXCL13 expression by blocking lactate-driven histone lactylation, thereby reversing the transcriptional reprogramming induced by lactate, as evidenced by reduced histone H3 lysine 18 lactylation (H3K18la) enrichment at the CXCL13 promoter. Taken together, these findings provide new insights into targeting metabolic-immune crosstalk and highlight the value of disrupting CD147–MCT1 interactions to improve immunotherapeutic responses in patients with melanoma.

Peptide drugs possess superior biocompatibility and excellent specificity, making them a reliable choice in clinical treatment. They exert critical roles in disease-associated metabolic reprogramming and immune modulation by activating cell signaling pathways, regulating metabolic processes, and immune cell functions. Notably, circular RNAs (circRNAs) have been shown to encode functional polypeptides. This finding offers new avenues for peptide drugs development. However, a summary of circRNA-encoded polypeptides as peptide drug applications is relatively lacking. Therefore, we summarize the latest scientific advances in peptide drugs in the realm of diseases, with the focus on circRNA-encoded polypeptides. We first delve into the functional mechanisms of peptide drugs within disease-associated metabolic reprogramming and immune response. Subsequently, we provide an overview of the delivery and modification strategies of peptide drugs. Additionally, we summarize the encoding mechanisms of circRNAs and review the drug-like applications of the polypeptides. We also highlight the potential challenges in the future development of circRNA-based polypeptide drugs. In summary, we offer a systematic review of the research progress on circRNA-encoded polypeptides, with the aim of providing novel perspective and ideas for the design and development of peptide drugs.

Assessing coronary microcirculation is crucial in the progression of hypertrophic cardiomyopathy (HCM), but it's often inadequate in clinical practice. This study investigates the role of coronary microcirculation, assessed via angiography-derived index of microvascular resistance (angio-IMR), in predicting clinical outcomes in HCM patients. We retrospectively measured angio-IMR in 422 HCM patients across two sites. The primary endpoint was major advance cardiovascular event (MACE), including cardiovascular death, heart failure readmission, life-threatening ventricular arrhythmias, septal reduction therapy or new-onset stroke. Over a mean follow-up of 43 ± 23 months, 63 patients (14.93%) experienced MACE. The mean angio-IMR value for the left anterior descending artery (LAD) was 22 ± 8. Using maximally selected log-rank statistic, 123 patients were stratified into the high LAD angio-IMR group, indicating microvascular dysfunction. Patients with LAD angio-IMR > 25 exhibited a higher incidence of MACE than those with LAD angio-IMR ≤ 25 (25.4% vs. 13.3%, p = 0.035). After adjusting for risk factors, elevated LAD angio-IMR remained an independent predictor of MACE (HR 1.779, 95% CI, 1.053–3.007, p = 0.031). Subgroup analysis showed consistent results. Our findings underscore that elevated LAD angio-IMR is a robust, independent indicator of adverse prognosis in HCM patients, highlighting the importance of evaluating LAD angio-IMR during coronary angiography for these patients.

Osteoarthritis (OA) is a chronic joint disease characterized by a complex pathological mechanism, including chondrocyte dysfunction, synovial inflammation, subchondral bone remodeling, and molecular regulation abnormalities. Key signaling pathways such as nuclear factor-κB, mitoase-activated protein kinase, and transforming growth factor-β are disrupted, leading to cytokine imbalance, oxidative stress, and excessive protease activity, which collectively contribute to cartilage degeneration. This review summarizes the potential causes of OA, focusing on cellular and structural abnormalities in cartilage, synovial tissue, and subchondral bone, as well as dysregulation of signaling pathways, gene regulation, and molecular mechanisms. Given the limitations of current diagnostic methods for OA, biomarkers may offer new hope. Emerging therapeutic strategies for OA include biologics, intelligent drug delivery, and tissue engineering, aiming to modulate the immune microenvironment while promoting cartilage repair. However, these approaches face challenges such as long-term safety and scalability. Future research may require deeper multidisciplinary collaboration and combination therapies to revolutionize the management of OA and improve patient outcomes.

Hepatocellular carcinoma (HCC) is a deadly disease characterized by a high mortality rate and resistance to conventional therapies, highlighting the need for novel therapeutic interventions. Given the multifaceted nature of HCC pathogenesis, a multitargeted and polypharmacological approach is crucial for effective treatment. This study reports the potent multitargeted and polypharmacological properties of ZAK-I-57, a benzoxazinone derivative, as a potential therapeutic option for HCC. In cell-based model, ZAK-I-57 demonstrated significant in vitro inhibition of proliferation in HCC cells. Utilizing PLC/PRF/5 tumor-bearing and HCC patient-derived tumor xenograft (PDTX) mouse models, we compared the efficacy of ZAK-I-57 with that of sorafenib, the current standard treatment. ZAK-I-57 demonstrated superior tumor suppressive effects at doses of 15 and 30 mg/kg, outperforming sorafenib. Western blot analysis revealed that ZAK-I-57 downregulated the oncogenic proteins EGFR and c-Myc, while promoting apoptosis by increasing Bax and decreasing Bcl-2 expression. Strikingly, ZAK-I-57 exhibited excellent ADMET properties, including high gastrointestinal absorption and good lipophilicity, along with an excellent safety profile, with no significant off-target toxicity in vital organs. In summary, our findings highlight ZAK-I-57 as a new and promising multitarget therapeutic agent for HCC, warranting further clinical investigation to improve patient outcomes.

Schizophrenia (SCZ) is a highly heritable neuropsychiatric disorder that affects ∼1% of people globally. Despite extensive research, there remains a lack of biomarkers for SCZ diagnosis and disease pathogenesis delineation. Cell-free DNA (cfDNA), which carries the genetic and epigenetic signatures of origin tissue cells, may provide a noninvasive method for biomarker discovery. We performed cfDNA 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) sequencing of plasma samples from 66 individuals with SCZ and 77 healthy controls. We identified 954 differentially 5mC methylated regions (DMRs) and 1474 differentially 5hmC hydroxymethylated regions (DhMRs) that showed distinct patterns between SCZ and control samples. Many DMRs and DhMRs were associated with genes specifically expressed in brain tissues and were enriched in neuronal functions, as well as were enriched for genome-wide association study (GWAS) of psychiatric and brain volume traits. Additionally, colocalization analysis revealed that DhMRs but not DMRs locations significantly overlapped with GWAS-identified genomic loci of SCZ. Moreover, we observed associations between DMRs and DhMRs with brain regional measurements depicted by magnetic resonance imaging. Together, our findings indicated that cfDNA 5mC and 5hmC patterns are accessible epigenomic signatures that can serve as potential biomarkers and to help delineate SCZ pathogenesis.

The PI3K/AKT/mTOR signaling axis is a pivotal regulator of key cellular functions, including proliferation, metabolism, survival, and immune modulation. In cancer, its dysregulation drives malignant transformation, tumor progression, therapeutic resistance, and immune evasion. Despite numerous studies, an integrated understanding of this pathway's multifaceted role in tumor biology and treatment remains incomplete. This review comprehensively outlines the oncogenic mechanisms governed by the PI3K/AKT/mTOR pathway, including its regulation of epithelial–mesenchymal transition, autophagy, apoptosis, glycolysis, ferroptosis, and lipid metabolism. We emphasize the dual role of autophagy, its interplay with therapeutic resistance, and its contextual impact on cancer dynamics. Moreover, we explore the epigenetic regulation of this axis by noncoding RNAs (miRNAs, lncRNAs, circRNAs) and its influence on tumor hallmarks. The review also highlights the pathway's involvement in modulating responses to chemotherapy, radiotherapy, and immunotherapy, as well as its role in remodeling the tumor microenvironment. We critically evaluate emerging therapeutic strategies targeting the PI3K/AKT/mTOR axis, including small-molecule inhibitors, phytochemicals, and nanoparticle-based systems. By elucidating the integrated landscape of this pathway, our review highlights its value as a central therapeutic target and offers insights into precision oncology approaches aimed at overcoming drug resistance and enhancing treatment efficacy.

Currently, there are many diseases worldwide that seriously affect women's health. Among these, gestational disorders and female cancers such as ovarian cancer are particularly notable for their high morbidity and mortality rates. Over the past decade, ferroptosis, a distinct form of programmed cell death primarily driven by iron-dependent phospholipid peroxidation, has been implicated in the pathogenesis of various female-related diseases. Despite many studies individually reporting that ferroptosis plays a crucial pathogenic role in common female disorders, there has yet to be a systematic overview addressing the mechanisms linking ferroptosis with women's health and disease. Thus, we herein provide a comprehensive review of the relationship between cellular pathways of ferroptosis and women's health and disease and describe the current progress of targeted therapy for ferroptosis. Following a succinct introduction to the disease, we summarize the regulatory role of ferroptosis in women's health and its implications for disease progression, with the aim of facilitating a clearer understanding of the relationship between ferroptosis and women's health. Finally, we discuss the emerging challenges and opportunities presented by various agonists or inhibitors targeting ferroptosis as potential therapeutic strategies for female-related diseases, providing additional protective approaches contributing to female health.

Astrocytes, as key support cells in the central nervous system, maintain homeostasis in the brain through mechanisms such as ionic homeostasis regulation, metabolic support, synaptic modulation, and neuroinflammatory regulation. Recent studies have shown that astrocyte dysfunction is closely related to the pathologic processes of various neurological diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and stroke. In this review, we comprehensively summarize the dual roles of astrocytes in neurological diseases: on one hand, their aberrant activation can exacerbate disease progression by mediating neuroinflammation, synaptic dysfunction, and blood–brain barrier disruption; on the other hand, their metabolic disorders, such as lipid droplet accumulation, mitochondrial dysfunction, and oxidative stress imbalance, further drive neurodegeneration. In terms of therapeutic strategies, interventions targeting astrocytes, such as modulation of activation phenotype, metabolic reprogramming, gene therapy, and innovative therapies based on exosomes and nanotechnology, show great promise. In the future, we may integrate multi-omics technologies and deepen clinical translational research to systematically analyze the spatial heterogeneity of astrocytes and their dynamic regulatory networks at different stages of the disease, in order to elucidate the precise mechanisms of their roles in the pathological process, and thus provide multidimensional theoretical support for the design of targeted therapeutic strategies.

This study aimed to investigate the efficacy, safety, and predictors of camrelizumab combined with carboplatin and nab-paclitaxel as first-line setting for patients with extensive-stage small-cell lung cancer (ES-SCLC). Camrelizumab plus carboplatin and nab-paclitaxel were administrated every 3 weeks for four to six cycles, followed by maintenance camrelizumab until intolerable toxicity or disease progression. The primary endpoint was 6-month progression-free survival (PFS) rate and secondary endpoints were objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety. We conducted the whole-exome and transcriptomic sequencing on available tumor samples to explore the potential predictive biomarkers. A total of 60 patients were included. Primary endpoint was met with 6-month PFS rate of 52.2%. The median PFS and OS were 7.1 and 18.1 months, respectively. The confirmed ORR and DCR were 73.3% and 93.3%, respectively. No unexpected adverse events were observed. Exploratory analysis showed that MUC17 alterations or high NEUROG1 expression were correlated with markedly shorter PFS and OS. Deeper investigation of transcriptomic data reveals two subsets with distinct immune features and therapeutic vulnerabilities. Collectively, this trial suggested that camrelizumab plus carboplatin and nab-paclitaxel might be an alternative first-line setting for ES-SCLC. Integration of multiomic data could highlight the complex mechanisms underlying chemo-immunotherapy responses.

Respiratory syncytial virus (RSV) ranks as the second leading cause of infant death globally and a significant contributor to morbidity and mortality among adults over 60 years old. The development of effective RSV vaccines and immunoprophylaxis remains a key focus. In our research, we formulated a protein-based vaccine known as MF59/preF, which combines the RSV pre-fusion (preF) antigen with an MF59-like oil-in-water adjuvant. Intramuscular (IM) or intranasal (IN) immunization of the MF59-adjuvanted preF protein vaccine elicited robust immune responses and neutralizing antibodies against both RSV A2 and RSV B strains, with the IM showing a particularly pronounced effect. Notably, IN immunization with MF59/preF demonstrated superior mucosal immunity, characterized by elevated levels of IgA antibodies and an increased frequency of tissue-resident memory T (T_RM) cells locally. More importantly, the combined IM and IN delivery of the MF59/preF vaccine synergistically enhanced antigen-specific humoral and cellular immune responses at both systemic and mucosal sites. Our study highlights the crucial impact of the route of administration and adjuvanted-protein subunit vaccines on triggering strong humoral and cellular immunity in mice.

This study evaluated the association between preoperative cognitive performance and postoperative delirium (POD) using a multicenter prospective cohort, and explored potential causality using Mendelian randomization (MR) analysis. We analyzed data from 2257 patients aged ≥ 75 years undergoing elective noncardiac and noncranial surgeries across 16 Chinese medical centers. Preoperative cognitive assessment using Mini-Cog revealed 28.4% of patients had cognitive impairment (score ≤ 2). POD occurred in 9.7% of patients, with higher incidence among those with cognitive impairment. Logistic regression demonstrated that cognitive impairment was significantly associated with increased POD risk (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.55–2.74; p < 0.001). This association persisted after adjustment for demographic, preoperative, and intraoperative factors, and was confirmed through propensity score matching and inverse probability treatment weighting analyses. A nearly linear inverse association was observed between Mini-Cog scores and POD incidence. Complementary MR analysis using 139 SNPs from European ancestry data suggested that higher cognitive performance might be associated with decreased delirium risk (inverse-variance weighted OR, 0.74; 95% CI, 0.59–0.93; p = 0.009). Although these results point to a potential link between preoperative cognition and POD, interpretation of causality should be approached with caution, particularly given differences in populations and genetic datasets.

Metabolic disorders play a crucial role in the occurrence of acute myocardial infarction (AMI). The objective of this research was to elucidate the characteristic metabolic profile of AMI and provide potential biomarkers for AMI. This study employed a targeted metabolomics approach utilizing the Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS) system to identify both hydrophilic and hydrophobic metabolites present in plasma samples. Among 1498 detected metabolites, 78 were the most significantly expressed in the AMI group. Functional synergy analysis showed prominent enrichment in the pathways of steroid hormone biosynthesis, biosynthesis of unsaturated fatty acids, bile secretion, and ABC transporters. The metabolites 2-Hydroxy-6-Aminopurine, 17α-Hydroxyprogesterone, and S-(methyl) glutathione have been identified as potential metabolic biomarkers linked to the pathogenesis of AMI. The diagnostic model that integrates these three metabolites exhibited exceptional performance in both the discovery and validation cohorts, attaining an area under the curve (AUC) value greater than 0.9. In addition, based on the follow-up data, we also found that the three metabolites were potential predictive biomarkers for poor prognosis of AMI. This study delineated the characteristic metabolic profile of AMI and assessed the value of metabolic molecules in the diagnosis and prognosis of AMI. This may provide insights for understanding the AMI occurrence and progression.

Macrophages are heterogeneous immune cells with diverse subtypes and tissue-specific distributions, displaying dynamic polarization states that critically govern their immunomodulatory functions and responses to environmental cues. As key regulators of innate and adaptive immunity, they originate from either embryonic progenitors or bone marrow-derived monocytes and exhibit remarkable plasticity in response to microenvironmental cues. Tissue-resident macrophages (e.g., Langerhans cells, Kupffer cells, microglia) display unique organ-specific functions, while inflammatory stimuli drive their polarization into proinflammatory (M1) or anti-inflammatory (M2) phenotypes along a functional continuum. This review systematically examines macrophage subtypes, their anatomical distribution, and the signaling pathways (e.g., NF-κB, STATs, PPARγ) underlying polarization shifts in acute and chronic inflammation. We highlight how polarization imbalances contribute to pathologies including neuroinflammation, liver fibrosis, and impaired tissue repair, particularly in aging contexts. Furthermore, we discuss emerging therapeutic strategies targeting macrophage plasticity, such as cytokine modulation, metabolic reprogramming, and subtype-specific interventions. By integrating recent advances in macrophage biology, this work provides a comprehensive framework for understanding their dual roles in immune regulation and tissue homeostasis, offering insights for treating inflammatory and age-related diseases through macrophage-centered immunomodulation.

Toll-like receptors (TLRs), which are critical components of innate immunity, play a significant role in immune responses and deepen our understanding of TLRs. TLRs are a group of transmembrane proteins with similar structures distributed on the cell membrane and endosomes. They trigger downstream acute or chronic inflammatory responses by recognizing different types of pathogen-associated molecular patterns and damage-associated molecular patterns. TLRs play pivotal regulatory roles in various tumor types. Over the past few decades, research on TLRs has become increasingly popular, and these molecules can not only directly recognize tumor components as potential targets to activate antitumor immune responses but also act as accomplices to tumor progression and even as driver genes in certain tumor types. Despite their importance, the mechanisms underlying their dual functions remain poorly understood, creating a gap in current research. Here, we summarize the latest advancements in TLR signaling pathways and their application in tumor therapy in recent years, and highlight the development prospects and potential of TLRs in tumor therapy. Moreover, this review underscores the critical regulatory roles of TLRs across various tumor types and explores their prospects in oncology, offering valuable insights for developing targeted therapies and improving cancer outcomes.

Therapeutic vaccinations that enhance human immunodeficiency virus (HIV)-specific immunity hold promise for reducing reliance on antiretroviral therapy (ART). We previously developed an adenovirus vector-infected peripheral blood mononuclear cell (AVIP) as a prophylactic strategy that enhanced cellular immunity in macaques and significantly reduced set-point and peak simian immunodeficiency virus (SIV) loads following SIV challenge. However, its therapeutic efficacy remains to be fully explored. In this study, we improved AVIP by enhancing adenovirus entry into peripheral blood mononuclear cells (PBMCs) through in vitro co-incubation with granulocyte-macrophage colony-stimulating factor (GM-CSF). We constructed adenoviruses carrying SIV group-specific antigen (Gag), envelope (Env), and polymerase (Pol) and evaluated the therapeutic potential of autologous AVIP infusion in acute SIV-infected macaques. Compared with ART alone, AVIP in combination with ART elicited robust cellular immunity against SIV, effectively controlled SIV replication during ART, and delayed viral rebound and acquired immunodeficiency syndrome (AIDS) progression after ART discontinuation. Notably, 80% of macaques in AVIP+ART group maintain plasma virus control for at least 100 days after ART interruption. This sustained viral control is associated with vaccine-induced Pol-specific immune responses and reduced CD38 expression on CD8⁺ T cells. These findings support further investigation of AVIP as a therapeutic strategy against acute HIV infection.

Psoriasis and ulcerative colitis are both autoimmune diseases with complex pathogenesis characterized by immune disorders. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase that acts as a key regulator of immune cell-mediated inflammation. Although studies have described the role of SHP2 in autoimmune diseases, its influence on the development of regulatory T cells (Tregs) was undefined, which plays a critical role in immune homeostasis. Here, we found that imiquimod (IMQ)-induced psoriasis symptoms were milder in Lck-Cre;SHP2^f/f mice than those in SHP2^f/f mice, including reduced inflammatory cell infiltration and keratinocyte proliferation. The reduced Th17/Treg ratio in psoriasis models in Lck-Cre;SHP2^f/f mice suggests that SHP2 regulates the balance of Th17/Treg. In vitro, the deficiency of SHP2 promotes the differentiation of T cells into Tregs. In the model of adoptive transfer colitis, the SHP2-deficient CD4⁺CD25⁻CD45RB^high T cells differentiated into a greater number of Tregs within the recipient mice, resulting in attenuated symptoms of colitis. Moreover, cotransfer experiments confirmed that the deficiency of SHP2 does not affect the immunosuppressive function of Tregs. These findings establish that SHP2 reduces Treg differentiation and further confirm that SHP2 inhibitors could be utilized in the treatment of autoimmune diseases.

5-Methylcytosine modification (m5C) is an important posttranscriptional regulatory mechanism of gene expression. Exhausted CD8+T cells contribute to the development of many major diseases; however, their exact role and relationship to m5C in systemic lupus erythematosus (SLE) remain unknown. In this study, we identified a CD7^highCD74^high CD8+T subgroup that were robustly expanded in SLE patients through single-cell transcriptome sequencing (scRNA-seq). CD7^highCD74^high CD8+T cells displayed exhausted features and exhibited a superior diagnostic value in SLE. Then, we explored the m5C landscape of SLE patients by performing m5C epitranscriptome sequencing (m5C-seq). ScRNA-seq and m5C-seq were conjointly analyzed to screen m5C-related therapeutic targets for SLE, and NOP2/Sun RNA methyltransferase 4 (NSUN4) was identified as a key regulator of SLE pathogenesis. Knockdown of NSUN4 downregulated CD74 expression via reduction of m5C and suppressed CD8+T cell exhaustion by declining CD44/mTOR (mechanistic target of rapamycin kinase)-mediated mitophagy. Finally, we verified that nanoparticle-delivered siRNA against Nusn4 decreased autoimmune reaction kidney damage in both spontaneous and pristane-induced SLE mouse models. In conclusion, we identify an exhausted CD7^highCD74^high CD8+T cell subset and propose the crucial role of NSUN4/CD74-induced dysregulation of mitophagy in SLE pathogenesis, and targeting NSUN4 is a promising treatment strategy for SLE patients.

Induction of cuproptosis in tumor cells is an emerging direction for cancer drug development. Plumbagin (PLB), a natural biological molecule, has anticancer activities, partially via copper-dependent mechanisms. But it remains unclear if PLB can induce cuproptosis in hepatocellular carcinoma (HCC). In this study, PLB showed HCC-suppressive activities and caused representative molecular phenotypes of cuproptosis, whereas tetrathiomolybdate, an inhibitor of cuproptosis, could alleviate these effects the most. The mRNA and protein expression levels of the primary hepatic copper exporter, ATPase copper transporting beta (ATP7B), decreased in PLB-treated HCC cells, which might cause the accumulation of intracellular copper and trigger cuproptosis. An upstream ATP7B-regulatory microRNA, microRNA-302a-3p (miR-302a-3p), was identified by quantification and validated by the overexpression/inhibition experiment and luciferase reporter assay. Moreover, PLB was found to reduce the protein level of DNA-methyltransferase 1 (DNMT1), thereby enhancing the promoter hypomethylation and the expression of miR-302a-3p. Gene manipulation experiments further demonstrated that ATP7B, miR-302a-3p, and DNMT1 mediated PLB-induced cuproptosis. Preliminary clinical analyses showed that low ATP7B expression levels were associated with better prognosis, supporting the importance of ATP7B-lowering therapeutic strategies in HCC. Together, our results indicate that PLB triggers HCC cuproptosis via the DNMT1/miR-302a-3p/ATP7B axis, providing a potential therapeutic strategy for HCC.

Staphylococcus aureus with varying virulence is often isolated from chronic rhinosinusitis (CRS) patients and impacts disease severity. Prophage-mediated virulence, particularly encoded by φSa3int (NM3) prophages, which often encodes human immune-evasion cluster genes is well known, but how a new prophage domestication impacts overall expression of core bacterial genes, and the expression of resident prophages is understudied. To understand this, we transduced a φSa3int prophage recovered from hyper-biofilm forming mucoid S. aureus (SA333) into a high-biofilm forming non-mucoid S. aureus (SA222) recovered from same CRS patient but at different time points. Upon φSa3int prophage domestication, we observed a significant upregulation of 21 exoproteins including human immune-evasion toxins and an intercellular adhesion protein B (IcaB). Further, φSa3int prophage domestication led to reduced phagocytosis implying φSa3int prophage mediates escape of S. aureus from human innate immunity. Our data further show that in addition to adding novel prophage-encoded virulence, φSa3int prophage domestication also affects the expression of non-prophage (bacterial) genes and suppresses expression of structural proteins of resident prophages. Since strains without prophage or with specific prophages have varying virulence and pathogenicity, targeted identification virulence factors associated with mobile genetic elements (MGEs) in addition to species identification may lead to better personalized therapy, particularly in chronic infections.

Lassa fever (LF) is a fatal hemorrhagic disease caused by the Lassa virus (LASV), which mainly spreads in Africa. As China's interactions with Africa become more frequent, the risk of LF being imported into China also rises, making the study of LASV increasingly urgent. In this study, the Lineage IV LASV strain was successfully isolated from the first imported case in China. Compared with the LASV genome, the isolated strain may exhibit greater infectivity and interspecies transmission capabilities. We successfully established BALB/c, C57BL/6, and AG129 mouse infection models and found that intranasal inoculation was the most stable infection method. Select the anti-LASV drug LHF-535 for preliminary evaluation, further confirming the stability of the model. In summary, the isolated strain exhibits enhanced transmission capabilities and may spread between mice via the respiratory tract, meriting greater attention and emphasis. This study will bridge the gap in China's independent P4-level pathogen isolation, meet national biosafety and strategic needs, and provide certain support for LASV research.

Immunotherapy has revolutionized the treatment of gastrointestinal (GI) cancers, but reliable biomarkers for predicting treatment efficacy remain limited. In this study, we explored the potential of blood microbiome and specific microbial taxa as novel biomarkers for predicting the efficacy of immunotherapy combined with chemotherapy in GI cancer patients through 16S rRNA sequencing. Our findings demonstrated that lower baseline alpha diversity and specific microbial compositions, particularly lower levels of Lactobacillus, were significantly associated with longer progression-free survival (PFS) in patients receiving immunotherapy combined with chemotherapy. Furthermore, we validated the reliability of Lactobacillus abundance as a predictor of PFS and treatment response in another independent patient cohort. Additionally, patients with increased or stable levels of Lactobacillus after immunotherapy combined with chemotherapy had superior PFS. Gavage of Lactobacillus rhamnosus (L. rhamnosus) el evated its blood level and enhanced the efficacy of immunotherapy in mouse models. Our results suggest that Lactobacillus may serve as a novel biomarker for predicting the efficacy of immunotherapy combined with chemotherapy and hold the potential as a PD-1 antibody sensitizer.

Artificial intelligence (AI) is revolutionizing biotechnology by transforming the landscape of therapeutic development. Traditional drug discovery faces persistent challenges, including high attrition rates, billion-dollar costs, and timelines exceeding a decade. Recent advances in AI—particularly generative models such as generative adversarial networks, variational autoencoders, and diffusion models—have introduced data-driven, iterative workflows that dramatically accelerate and enhance pharmaceutical R&D. However, a comprehensive synthesis of how AI technologies reshape each key modality of drug discovery remains lacking. This review systematically examines AI-enabled breakthroughs across four major therapeutic platforms: small-molecule drug design, protein binder discovery, antibody engineering, and nanoparticle-based delivery systems. It highlights AI's ability to achieve >75% hit validation in virtual screening, design protein binders with sub-Ångström structural fidelity, enhancing antibody binding affinity to the picomolar range, and optimize nanoparticles to achieve over 85% functionalization efficiency. We further discuss the integration of high-throughput experimentation, closed-loop validation, and AI-guided optimization in expanding the druggable proteome and enabling precision medicine. By consolidating cross-domain advances, this review provides a roadmap for leveraging machine learning to overcome current biopharmaceutical bottlenecks and accelerate next-generation therapeutic innovation.

Mitochondria are central regulators of cellular energy metabolism, and their functional integrity is essential for maintaining cellular homeostasis. Mitochondrial quality control (MQC) encompasses a coordinated network of mitochondrial biogenesis, dynamics (fusion and fission), and selective autophagy (mitophagy), which together sustain mitochondrial structure and function. Under physiological conditions, MQC ensures the removal of dysfunctional mitochondria, restricts excessive reactive oxygen species production, and modulates apoptosis, thereby supporting the high energy demands of organs such as the heart and brain. Disruption of MQC contributes to the onset and progression of various diseases, including neurodegenerative disorders, cardiovascular pathologies, and metabolic syndromes, largely through accumulation of damaged mitochondria and impaired metabolic signaling. While the core components of MQC have been characterized, the mechanistic interplay among its modules and their disease-specific alterations remain incompletely defined. This review provides an integrated overview of the molecular pathways governing mitochondrial biogenesis, dynamics, and mitophagy, with a focus on their cross-talk in maintaining mitochondrial homeostasis. We further discuss how MQC dysfunction contributes to disease pathogenesis and examine emerging therapeutic approaches aimed at restoring mitochondrial quality. Understanding the regulatory logic of MQC not only elucidates fundamental principles of cellular stress adaptation but also informs novel strategies for disease intervention.

RNA epigenetics, also referred to as epitranscriptomics, has emerged as a critical regulatory layer in cancer biology, extending beyond the scope of traditional DNA and histone modifications. It encompasses a series of dynamic posttranscriptional processes—including RNA biosynthesis, splicing, transport, stability, degradation, translation, and chemical modifications—orchestrated by RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs). Collectively, these mechanisms influence mRNA fate, shape transcriptional output, and reprogram the tumor microenvironment. Importantly, both coding RNA and ncRNA are themselves subjected to epigenetic regulation, forming intricate feedback loops that contribute to oncogenesis, immune evasion, metastasis, and therapeutic resistance. In this review, we systematically synthesize the current understanding of RNA metabolism and RNA epigenetic modifications during tumor progression, with a particular focus on the roles of RBPs and RNA modifications. Furthermore, we highlight recent advances in RNA-based therapeutic strategies, including mRNA vaccines, antisense oligonucleotides, siRNAs, and circRNA scaffolds. These innovative approaches offer promising avenues for targeting transcriptionally active yet genomically “undruggable” cancer drivers. Together, our synthesis provides a comprehensive framework for understanding RNA epigenetics in tumor biology and lays the groundwork for precision oncology guided by transcriptome plasticity.

Chronic pain imposes incalculable health and economic burdens, affecting more than 30% of the global population in published studies. Optimal management of chronic pain is imperative for individuals experiencing such distress. Nevertheless, the current approaches to chronic pain assessment and treatment fail to meet clinical requirements. In recent years, there has been a growing recognition of the need for precision medicine approaches to effectively manage chronic pain. Chronic pain can be classified into three categories: nociceptive (resulting from tissue injury), neuropathic (caused by nerve injury), or nociplastic (arising from a sensitized nervous system). These classifications significantly impact the evaluation and treatment decisions at all levels. Significantly, in practice, there is substantial overlap in chronic pain mechanisms among patients and within different types of chronic pain. The application of precision medicine is imperative in the management of chronic pain. This review offers a comprehensive overview of the distinctive molecular mechanisms underlying nociceptive, neuropathic, and nociplastic pain, including immune responses, ion channels, monoaminergic imbalance, and neuroinflammation. Subsequently, we summarized the status quo of nociceptive, neuropathic, and nociplastic pain manipulation. Last, we explored the advances in pain management strategies for chronic pain that are making significant progress toward their clinical implementation.

Paying attention to the mental health of perinatal women is helpful in improving their quality of life. However, the existing research pays less attention to the heterogeneity of its negative emotional trajectory and the identification of high-risk groups. This study recruited 860 perinatal women from four large hospitals in Chongqing from March 2018 to January 2019. They were followed up by structured questionnaires in the first trimester, second trimester, third trimester, and about 6 weeks after delivery. The growth mixture model was used to analyze the developmental trajectory of negative emotions, and six machine learning algorithms were used to establish a high-risk negative emotion recognition model. The performance of the model was comprehensively evaluated by five performance indicators. The SHAP algorithm was used to explain the model. Negative emotional trajectories were divided into four categories: low-stable anxiety group, gradually increasing high-anxiety group, mild sustained depression group, and high-progressive depression group. The extreme gradient boosting model performed best, with the highest prediction performance score (24 points). In summary, the negative emotional trajectory of perinatal women is dynamic and heterogeneous, and the prediction model based on machine learning may play an important role in identifying high-risk negative emotions.