Abstract:The 2025 Nobel Prize in Physiology or Medicine was awarded to Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi in recognition of their groundbreaking contributions to unraveling the mechanisms of peripheral immune tolerance. Regulatory T cells (Tregs), as the core components maintaining peripheral immune tolerance, exhibit high plasticity and heterogeneity. Dysregulation of Treg function is closely associated with autoimmune diseases, tumor progression, and transplant rejection. Forkhead box protein P3 (FOXP3) is a key transcription factor that controls the development and function of Tregs. This review discusses the classification of Tregs into thymic-derived Tregs (tTregs), peripherally induced Tregs (pTregs), and in vitro-induced Tregs (iTregs). It also elaborates on how Treg cells exert their inhibitory functions through multiple pathways, including the secretion of inhibitory factors, metabolic interference via competitive uptake of IL-2, and direct cell-cell contact.induced Tregs (iTregs). It also elaborates on how Treg cells exert their inhibitory functions through multiple pathways, including the secretion of inhibitory factors, metabolic interference via competitive uptake of IL In recent years, significant advances have been made in Treg and FOXP3 research, progressively deepening our understanding of Treg plasticity. Investigations have revealed their capacity to adapt and acquire features of effector T helper cell subsets—such as Th1, Th2, and Th17—under specific microenvironmental cues. This plasticity also poses challenges for therapeutic interventions, as Tregs can potentially lose their suppressive function and acquire pro-inflammatory properties, thereby exacerbating disease pathology. Furthermore, the concept of tissue-specific Treg specialization has emerged, highlighting distinct functional subsets resident in organs such as the gut, adipose tissue, and tumors. For instance, gut-resident Tregs maintain tolerance to commensal bacteria and dietary antigens, while tumor-infiltrating Tregs promote immune evasion by suppressing anti-tumor immunity. Concurrently, studies on the metabolic and epigenetic regulation of Tregs, including post-translational modifications of FOXP3 such as acetylation and ubiquitination, have uncovered intricate layers of control over their stability and function. Building upon these fundamental insights, this review synthesizes FOXP3-targeted therapeutic strategies. These encompass approaches to enhance Treg function in autoimmune diseases and transplantation, including adoptive cell therapies and pharmacological interventions. Conversely, strategies to antagonize Treg-mediated immunosuppression in oncology, such as immune checkpoint blockade, are discussed. Notably, the development of programmable engineered Tregs represents a particularly promising frontier for achieving antigen-specific immune modulation with enhanced precision and efficacy. However, the field of Treg research continues to grapple with several complex challenges. The deeper, underlying regulatory networks governing Treg biology remain incompletely understood. A comprehensive resolution of Treg heterogeneity is still lacking, and significant hurdles exist in maintaining the stability and function of Tregs during in vitro expansion and culture. Furthermore, the precision and efficacy of translating these findings into clinical applications require substantial improvement. Consequently, both the development of Treg-targeting pharmacological agents and the refinement of Treg-based cellular therapies demand more profound exploration. The ultimate goal is to overcome these obstacles and achieve transformative, breakthrough clinical outcomes in the foreseeable future.

Abstract:This paper presents a comprehensive exploration of the IPDPS teaching concept—a framework built upon the 5 core principles of interdisciplinarity, practicality, diversity, process-oriented, and soul-forging—and its systematic implementation in the general education course "Biology in Daily Life" at Sun Yat-sen University. Developed over 8 years of iterative practice, this educational model is designed to address critical challenges in cultivating top innovative talents within higher education. It specifically targets the overcoming of disciplinary barriers, the disconnection between academia and industry, the limitations of one-way knowledge transmission, the rigidity of traditional evaluation systems, and the lack of value guidance. The curriculum is innovatively structured around four life-centric modules—birth, aging, illness, and food—which seamlessly integrate cutting-edge advancements in life sciences with interdisciplinary knowledge, making complex biological concepts accessible and relevant to students from diverse academic backgrounds. Pedagogically, the course employs a rich array of teaching methods to activate student engagement and foster higher-order thinking skills. These include case-based learning? driven by real-world problems, multi-sensory interactive experiences?, storytelling? to illustrate scientific discovery processes, and contrastive analysis? of ethical dilemmas in science. A cornerstone of the implementation is a multi-tiered practical teaching system, encompassing mandatory in-class experiments, optional social investigations, corporate visits, and face-to-face sessions with industry leaders. This structure ensures learning extends from the classroom to real-world societal and industrial contexts. A significant reform is the shift from a summative to a process-oriented evaluation system. This system diversifies assessment methods and incorporates multiple evaluators, including teacher assessment, self-assessment, and structured peer review using detailed rubrics. This approach aims to stimulate intrinsic motivation, foster a growth mindset, and provide a more holistic measurement of student development. Fundamentally, the course deeply integrates value-shaping elements? into its fabric. By incorporating themes of national identity, scientific spirit, bioethics, and cultural confidence through specific cases, the course forges students" sense of social responsibility and ethical reasoning, ensuring their innovative capacities are guided by a strong moral compass. Assessment data from 2017 to 2024 demonstrates significant positive outcomes. Course satisfaction ratings have shown a remarkable increase, rising from 80.5% to 96.8%. Survey data from 245 students (2021–2024) indicates that the course effectively broadens interdisciplinary horizons, enhances independent thinking and problem-solving abilities, and successfully integrates knowledge acquisition with capacity building and value orientation. The course has successfully functioned as an "initial incubator and screening mechanism"? for identifying and nurturing talented individuals, with some students even shifting their academic focus to biology as a result. In conclusion, the "Biology in Daily Life" course, underpinned by the IPDPS framework, provides a replicable and scalable paradigm for educational innovation in cultivating elite innovators. It represents a successful model for achieving the organic unity of knowledge impartation, ability cultivation, and value shaping in higher education. Future work will focus on optimizing differentiated content design for diverse student backgrounds, deepening practical teaching experiences, and establishing long-term tracking mechanisms for learning outcomes.

Abstract:Regulatory T cells (Treg cells) have reshaped modern immunology by establishing the conceptual and mechanistic foundation of peripheral immune tolerance. Since the pioneering identification of CD4⁺CD25⁺ suppressive T cells by Shimon Sakaguchi and the subsequent discovery of the lineage-defining transcription factor forkhead box P3 (Foxp3) by Mary E. Brunkow and Fred Ramsdell, Treg cells have been recognized as indispensable guardians of immune homeostasis. These advances collectively clarified that central tolerance alone is insufficient to eliminate all self-reactive lymphocytes, and peripheral tolerance—critically mediated by Treg cells—serves as a second barrier preventing pathological autoimmunity. Contemporary research has therefore expanded the functional and therapeutic significance of Treg cells across the fields of autoimmunity, cancer, transplantation, and tissue repair. Treg cells originate from two major developmental pathways: thymus-derived Treg (tTreg) cells, which arise from high-affinity self-reactive TCR interactions in the thymus, and peripheral Treg (pTreg) cells, which are induced in mucosal and other peripheral tissues via antigen stimulation under tolerogenic cytokine cues such as IL-2 and TGF-β. Their differentiation is orchestrated by a multilayered transcriptional and epigenetic network within the Foxp3 locus, including CNS0-CNS3 elements that integrate TCR, cytokine and environmental signals to support lineage stability. Treg cells are identified by a combination of surface and intracellular markers—CD25, CD127^low/-, CTLA-4, GITR, TNFR2, CD39/CD73, and Foxp3—although marker specificity varies with context, activation state, and species. Their notable heterogeneity enables Treg cells to adopt Th1-, Th2-, Th17- or Tfh-like programs through transcription factors such as T-bet, GATA3, RORγt and Bcl6, thereby permitting precise suppression of corresponding effector responses. Tissue-resident Treg subsets in adipose tissue, skin, skeletal muscle and the CNS have emerged as highly specialized regulators that integrate local metabolic and stromal signals, contributing not only to immunosuppression but also to tissue regeneration. Mechanistically, Treg cells maintain tolerance through three synergistic strategies: (1) secretion of suppressive cytokines (IL-10, TGF-β, IL-35) and cytotoxic mediators (granzyme B, perforin); (2) cell-contact-dependent interactions via CTLA-4, PD-1/PD-L1, and LAG-3 to limit dendritic cell maturation and T-cell activation; and (3) metabolic regulation including IL-2 consumption, adenosine production via CD39/CD73, cAMP transfer through gap junctions, and adaptation to hypoxic or nutrient-restricted microenvironments. Dysregulation of Treg cell quantity or function contributes directly to pathogenesis across a spectrum of diseases. In autoimmune diseases such as type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis, impaired Foxp3 stability, epigenetic abnormalities, defective IL-2 signaling or inflammatory cytokine exposure undermine Treg suppressive capacity, facilitating excessive autoreactive T- and B-cell activation. In contrast, within the tumor microenvironment, Treg cells are often enriched through chemokine axes such as CCL22-CCR4 and reinforced by interaction with myeloid-derived suppressor cells and tumor-associated macrophages. Their enhanced metabolic fitness and suppressive phenotype enable tumors to evade immune destruction. In transplantation, Treg cells are essential for promoting graft tolerance, restraining effector T-cell activation, and facilitating tissue repair after injury. Rapid therapeutic progress has been driven by Treg-based immunomodulation. Polyclonal Treg adoptive transfer has demonstrated safety and preliminary efficacy in type 1 diabetes, autoimmune disorders, solid-organ transplantation, and graft-versus-host disease. Gene-engineered Treg therapies, including antigen-specific CAR-Treg and TCR-Treg platforms, offer superior precision and stability, enabling targeted suppression at disease sites. Additional strategies—including low-dose IL-2 therapy, small-molecule modulation, and selective depletion of intratumoral Treg using antibodies against CCR4, CCR8, CTLA-4 or CD25×TIGIT bispecifics—further expand the translational landscape. Collectively, advances in Treg biology—from lineage ontogeny and molecular regulation to specialized functions and therapeutic engineering—highlight Treg cells as central orchestrators of immune equilibrium. Continued integration of single-cell multi-omics, systems immunology and gene-editing technologies is expected to accelerate the development of highly specific, durable and safe Treg-centered therapies, ultimately enabling precision control of immune tolerance in autoimmunity, transplantation and cancer.

Abstract:Objective Pioneer transcription factors (PTFs) possess the unique ability to recognize and bind their target DNA sequences within compacted nucleosomal DNA, thereby initiating chromatin opening and gene expression. They play pivotal roles in fundamental biological processes such as embryonic development, cellular reprogramming, and tumorigenesis. The specific regulatory mechanism by which nucleosomal rotational positioning governs PTF-nucleosome interactions remains inadequately elucidated. This study aims to systematically investigate the role of the rotational orientation of motifs in PTF-nucleosome binding.Methods We employed a DNA deformation energy model to predict the rotational positioning of DNA on nucleosomes. We analyzed high-throughput in vitro data from the NCAP-SELEX assay, which profiles the binding landscapes of numerous transcription factors to nucleosomal DNA. For in vivo analysis, we integrated genome-wide binding data (ChIP-seq) and nucleosome positioning data (MNase-seq) for eight well-characterized pioneer factors (OCT4, SOX2, KLF4, GATA4, MYOD1, FOXA1, CEBPA, and ASCL1) in human cells. Binding motifs were classified as "TF-bound" if they overlapped with ChIP-seq 峰s and "TF-unbound" otherwise. DNA bendability profiles and Fast Fourier Transform (FFT) analysis were used to assess rotational positioning patterns around these motif sites. This analytical framework was further applied to specific biological contexts, including cellular reprogramming from IMR90 fibroblasts to induced pluripotent stem cells (iPSCs) and the differentiation of human embryonic stem cells (hESCs) to human neuroectodermal cells (hNECs).Results Our in vitro analysis revealed a strong dependence of transcription factor binding on the rotational orientation of TF-binding motifs. For SOX7, the unbound motifs at specific enrichment 峰s exhibited a rotational phase clearly opposite to that of the SOX7-bound motifs. Similarly, analysis of P53 binding sequences confirmed that successful binding in vitro correlated with model-predicted exposure of the DNA minor groove at the motif center, consistent with P53"s binding mode. Genome-wide in vivo analysis of the eight PTFs showed that their DNA binding motifs were generally associated with DNA sequences exhibiting significant 10-bp periodicity in bendability, suggesting an inherent potential for nucleosome association. Crucially, for most factors (except ASCL1), the average rotational positioning preferences were remarkably similar between TF-bound and TF-unbound motifs. This indicates that, at a global genomic level, rotational positioning is not the primary determinant dictating whether a nucleosomal motif is bound by its cognate PTF in vivo. This phenomenon persisted during cellular reprogramming (IMR90 to iPSC), where the rotational positioning of OSKM factor motifs bound versus unbound in nucleosomal regions showed no significant overall difference. Interestingly, during hESC differentiation to hNECs, SOX2 binding sites underwent comprehensive reprogramming. In hNECs, the rotational positioning of nucleosomal SOX2-bound motifs was significantly different and, unexpectedly, opposite to the general preference observed in hESCs and for unbound motifs in hNECs, suggesting a cell context-dependent rewiring of binding mechanisms.Conclusion This study suggests a distinction in the role of DNA rotational positioning in TF-nucleosome binding between in vitro and in vivo environments. While rotational positioning critically governs the binding efficiency of factors like SOX7 and P53 in simplified in vitro systems, PTFs in vivo appear to overcome this steric hindrance at the binding interface. The ability of PTFs to bind nucleosomal motifs, even when key interaction surfaces are partially buried, might stem from their unique structural properties (e.g., intrinsically disordered regions, DNA distortion/binding domains), nucleosome breathing which transiently exposes DNA, and potential cooperativity with other factors. Our results highlight the unique capacity of pioneer factors to drive chromatin openness through mechanisms beyond rotational positioning.

Abstract:Methamphetamine (METH) addiction is a severe and increasingly prevalent neuropsychiatric disorder for which current diagnostic and therapeutic approaches remain limited and predominantly symptom-oriented. Exercise, as a safe, accessible and cost-effective non-pharmacological intervention, has emerged as a promising strategy to ameliorate METH-induced neurotoxicity and addiction-related behaviors. Growing evidence indicates that these benefits are closely linked to the regulation of exercise-induced biomarkers, defined as molecular indicators whose expression or activity is dynamically altered during or after physical activity. This review focuses on the core regulatory role of exercise-induced biomarkers in METH addiction and systematically summarizes their involvement in key neurobiological pathways, outlining molecular pathological mechanisms such as dysregulation of dopamine, glutamate and GABA neurotransmitter systems, neuroinflammation and oxidative stress, and epigenetic remodeling, and emphasizing how these processes converge on changes in candidate biomarkers in the brain and periphery. On this basis, the review describes how exercise modulates neural plasticity, neurotransmitter systems, inflammation and oxidative stress through biomarkers such as brain-derived neurotrophic factor (BDNF), exerkines, inflammatory cytokines, metabolites and non-coding RNAs, with particular attention to neurotrophic and immune-related markers, microRNAs and other epigenetic regulators that can reverse METH-induced synaptic and structural abnormalities and promote recovery of cognitive and emotional functions. Advances in high-throughput omics technologies, including transcriptomics, metabolomics and multi-omics integration, are summarized to illustrate the screening and identification of key exercise-responsive biomarkers. Studies in METH-addicted animal models have revealed differentially expressed genes, signaling pathways (e.g., PI3K-Akt, mTOR, Wnt) and core nodes such as NFKBIA and CXCL12 that may mediate the protective effects of exercise. The review further discusses the potential of exercise-mediated biomarkers as objective indicators for diagnosis, dynamic monitoring of therapeutic efficacy and patient stratification. Multi-gene diagnostic models based on peripheral samples (e.g., hair follicles, blood) demonstrate how biomarker panels can distinguish non-recovered, almost-recovered and healthy individuals, providing a molecular basis for staging METH use disorder and evaluating the impact of exercise interventions. The temporal dynamics of biomarker changes before and after exercise are highlighted, underscoring the value of longitudinal monitoring of factors such as BDNF, immune-related genes and circulating microRNAs to capture treatment-relevant windows of plasticity. In addition, the underlying molecular basis of exercise as an adjunct therapy and gene-targeted exercise strategies that leverage individual biomarker and gene expression profiles to optimize exercise prescriptions are summarized. Current conceptual and technical challenges are outlined, including heterogeneity of biomarker responses, individual variability, assay sensitivity and specificity, and gaps between preclinical findings and clinical application, together with future directions for integrating exercise with multi-omics, artificial intelligence-assisted biomarker discovery and, prospectively, gene-editing-based interventions. Particular emphasis is placed on the need to standardize exercise protocols, incorporate stage-specific and sex-sensitive designs, and combine exercise with pharmacotherapy and psychosocial rehabilitation in real-world clinical settings across diverse healthcare systems. Overall, this review aims to provide a comprehensive and integrated mechanistic framework and updated theoretical support for the application of exercise-mediated biomarkers in the diagnosis, therapeutic effect monitoring and personalized intervention of METH addiction, and to offer new and clinically relevant insights into the development of precision medicine strategies for substance use disorders.

Abstract:Objective Osteoporosis is a progressive metabolic bone disorder characterized by reduced bone mass and microarchitectural deterioration, leading to increased skeletal fragility and susceptibility to fracture. Conventional diagnostic and risk-assessment approaches, such as dual-energy X-ray absorptiometry (DXA) and the FRAX? algorithm, remain limited because they rely primarily on bone mineral density (BMD) and a restricted set of clinical factors, failing to capture the multidimensional determinants of bone strength. This study aimed to develop and validate a deep learning–based multi-dimensional feature fusion model that integrates heterogeneous biological, structural, functional, and genetic information to improve the early identification of osteoporosis and enhance fracture risk prediction.Methods A total of 12 856 participants were aggregated from three major data repositories: the International Osteoporosis Foundation database, a clinical research database on osteoporosis, and a large-scale medical informatics dataset. A unified data-extraction protocol was applied to ensure cross-database harmonization, followed by quality control, variable standardization, and missing-data handling using multiple imputation by chained equations (MICE). A multimodal deep learning framework was constructed to integrate six categories of features: BMD measurements, quantitative bone microarchitecture parameters, bone turnover biomarkers, established clinical risk factors, osteoporosis-related genetic polymorphisms, and sensor-derived balance and gait metrics. A multi-task learning strategy was adopted to simultaneously predict osteoporosis status and 10-year fracture probability. Model training used five-fold cross-validation, and external validation was conducted in an independent clinical cohort. Model performance was benchmarked against DXA alone and the FRAX tool.Results In the internal test cohort, the proposed model achieved an AUC of 0.936 (95% CI: 0.927–0.945), with a sensitivity of 87.5% and a specificity of 91.2%, significantly outperforming DXA alone (AUC=0.889) and FRAX (AUC=0.842) (both P<0.05). External validation yielded an AUC of 0.918 (95% CI: 0.905–0.931) and demonstrated strong calibration (Brier score=0.087). SHAP analyses revealed that, beyond BMD, key predictors included trabecular separation, serum C-terminal telopeptide of type I collagen, balance-related metrics, gait speed, and specific SNPs within the RANKL and VDR loci. A simplified model incorporating only BMD, clinical features, and bone turnover markers preserved high accuracy (AUC=0.917), underscoring its feasibility for resource-limited clinical environments.Conclusion The deep learning–based multi-dimensional feature fusion model markedly enhances the precision and individualization of osteoporosis assessment compared with traditional tools. By integrating biological, structural, metabolic, genetic, and functional dimensions of bone health, the model provides a comprehensive representation of skeletal integrity and robustly improves both diagnostic accuracy and fracture risk prediction. Its strong generalizability across demographic subgroups highlights its clinical applicability. This work offers a promising direction for developing next-generation intelligent decision-support systems that may meaningfully improve osteoporosis screening, risk stratification, and preventive care.

Abstract:Ischemic stroke (IS) accounts for approximately 80% of all stroke cases and is a leading cause of death and long-term disability worldwide. Its core pathological mechanism involves the interruption of cerebral blood flow, leading to neuronal cell death and ischemic tissue necrosis in the brain, which is associated with multiple molecular processes including apoptosis, inflammation, and oxidative stress. This review systematically discusses the classification of HDACs, the mechanisms of action of HDAC inhibitors, and their multiple effects in inhibiting cell apoptosis, regulating neuroinflammation, repairing the blood-brain barrier, and improving cognitive function following IS. HDACs function by removing acetyl groups from histone lysine residues, leading to chromatin condensation and gene silencing. The HDAC family is classified into four classes: class I (HDAC1, 2, 3, 8), class IIa (HDAC4, 5, 7, 9), class IIb (HDAC6, 10), and class IV (HDAC11), with class III being the NAD?-dependent sirtuins. Histone deacetylase inhibitors (HDACi) exert significant neuroprotective effects following ischemic stroke through a multi-target, multi-pathway synergistic mechanism. The core mechanisms include inhibition of neuronal apoptosis, regulation of neuroinflammation, protection of the blood-brain barrier (BBB), and improvement of cognitive impairments (PSCI). HDACi regulate gene expression epigenetically by upregulating genes such as p21/CIP1, leading to cell cycle arrest, while also modulating apoptosis-related proteins by inhibiting pro-apoptotic signaling pathways, thereby reducing neuronal cell death. In terms of neuroinflammation, HDACi suppress NF-κB and activate Nrf2 pathways, decreasing the release of pro-inflammatory cytokines and preventing the pro-inflammatory polarization of microglia and macrophages, thus modulating the inflammatory response. Regarding BBB protection, HDACi regulate the expression and restoration of tight junction proteins such as Occludin and Claudin-5, while inhibiting the release of destructive factors like MMP-9, alleviating vasogenic edema, and maintaining BBB integrity. Furthermore, HDACi promote the transcription of neurotrophic factors and synaptic-associated genes, enhancing neuroplasticity and repairing neuronal networks, ultimately improving cognitive functions. Therefore, HDACi demonstrate great potential as a multifaceted therapeutic strategy for ischemic stroke. HDAC inhibitors (HDACis) represent a powerful multi-target therapeutic approach that transcends the limitations of traditional thrombolytic therapies. HDACis represent a powerful multi-target therapeutic approach that transcends the limitations of traditional thrombolytic therapies, which are hampered by a narrow time window and risks of reperfusion injury. Histone acetylation is increased by HDACis, which relaxes chromatin and reactivates protective gene transcription. Their selectivity and chemical structure are used to classify them. Trichostatin A (TSA) and sodium butyrate (SB), a short-chain fatty acid, are examples of broad-spectrum inhibitors that are effective in lowering infarct volume and reducing neuroinflammation. More selective inhibitors, including tubastatin A (HDAC6-selective) and entinostat (class I-selective), may have fewer adverse effects while increasing efficacy. By suppressing apoptosis by modifying the p53, Bcl-2, and JNK pathways, reducing neuroinflammation by blocking NF-κB and NLRP3 activation, preserving the integrity of the blood-brain barrier by strengthening tight junction proteins, and promoting synaptic plasticity, neurogenesis, and the expression of neurotrophic factors like BDNF, these inhibitors provide neuroprotection through a variety of interrelated mechanisms.Despite their great potential, HDACis" clinical translation is fraught with difficulties, mostly because of non-selective inhibition-related adverse effects such as hepatotoxicity and gastrointestinal problems with valproic acid (VPA). In order to accomplish targeted delivery to the brain, future research is consequently shifting toward the development of highly selective inhibitors, refining dosing regimes, and utilizing cutting-edge drug delivery technologies like nanoparticles. In summary, the development of effective neuroprotective and neurorestorative treatments for IS may be greatly aided by a nuanced, spatiotemporally accurate understanding of HDAC activities and the judicious use of subtype-selective HDACis.

Abstract:Parkinson"s disease (PD), the second most prevalent neurodegenerative disorder worldwide after Alzheimer"s disease , is pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the abnormal intracellular aggregation of α-synuclein into Lewy bodies. Traditionally, the clinical symptoms of PD have focused on motor dysfunction, which includes characteristic signs such as resting tremor, rigidity, bradykinesia, and postural instability. However, increasing evidence from both clinical and basic research suggests that the clinical presentation of PD is highly diverse, with neuropsychiatric complications representing a significant and unavoidable aspect of the disease"s overall burden. From the perspective of clinical phenotypes, the range of neuropsychiatric symptoms associated with PD is extensive, primarily including depressive disorders, generalized anxiety, apathy, impulse control disorders, and cognitive impairments related to executive function and memory. Notably, emotional and cognitive dysfunctions often manifest years prior to the onset of motor symptoms. This clinical observation indicates that the pathological processes of PD may originate within the non-motor circuits of the central nervous system (CNS), particularly in neural networks closely linked to emotional regulation and cognitive function. As one of the human body"s most lipid-rich organs, the CNS comprises lipids that account for approximately 50%–60% of the dry weight of brain tissue. These lipid molecules serve not only as structural components but also actively participate in the formation of cell membrane phospholipid bilayers, myelin sheath insulation layers, and various signal transduction complexes. From a functional perspective, lipids not only provide the structural foundation necessary for maintaining neuronal membrane fluidity, synaptic plasticity, and ion channel activity, but also act as essential molecules in energy metabolism, signal transduction, and epigenetic regulation. Notably, the frontal cortex—particularly its evolutionarily specialized prefrontal cortex (PFC)—functions as the brain"s "executive center for cognition and emotion". This region is pivotal for higher cognitive functions, including working memory, decision-making, and behavioral inhibition, as well as for the complex regulation of emotions, such as reward and risk assessment. This region displays an exceptionally high synaptic density and is abundant in structural lipids, including unsaturated fatty acids and cholesterol, which makes it particularly vulnerable to disturbances in lipid metabolism. In PD research, lipid imbalance has become a central focus. As investigations progress, the importance of lipid metabolic pathways becomes increasingly apparent. Simultaneously, pharmacological therapies aimed at lipid regulation show considerable efficacy in addressing cognitive and emotional deficits associated with PD. In light of this, the present study utilizes bioinformatics analysis to identify differentially expressed genes in the peripheral blood of PD patients, demonstrating significant enrichment in processes such as chronic depression, cholesterol metabolism, fatty acid metabolism, AMPK signaling pathways, and insulin resistance. Expanding on this groundwork, the present review systematically explores the connections between dysregulated lipid metabolism and metabolic reprogramming in cognitive and emotional impairments associated with PD. Through the analysis findings, intervention approaches focusing on various fundamental pathological pathways such as neuroinflammation, mitochondrial dysfunction, imbalance in lactate homeostasis, and disrupted protein homeostasis are suggested. These proposals provide innovative perspectives for advancing mechanistic investigations and therapeutic advancements targeting cognitive and emotional disorders in PD.

Abstract:Spinal cord injury (SCI) is a highly disabling trauma of the central nervous system, characterized by a complex pathological process involving intertwined multiple mechanisms. Key pathological events include excessive activation of neuroinflammation, oxidative stress injury, neuronal apoptosis, autophagic dysfunction, and energy metabolism imbalance, which severely disrupt the integrity of spinal cord neural function and significantly reduce patients" quality of life. Currently, clinical neurorepair strategies for SCI have limited efficacy and are difficult to achieve synergistic intervention targeting multiple pathological links. Therefore, exploring novel core therapeutic targets and precise intervention regimens has become an urgent need in this field. The Sirtuins family (SIRT1–SIRT7), as NAD?-dependent deacetylases, play a central role in critical biological processes such as cellular metabolism regulation, immune homeostasis maintenance, and stress injury repair, and have been identified as potential intervention targets for neurological diseases. This review systematically summarizes the cellular localization and core biological functions of each member of the Sirtuins family, with a focus on their regulatory roles and molecular mechanisms in the pathological process of SCI: SIRT1, 3, 5, and 6 inhibit the excessive activation of the NF-κB pathway and block NLRP3 inflammasome assembly through deacetylation modification, thereby participating in the regulation of neuroinflammation after SCI; meanwhile, they alleviate oxidative stress injury in spinal cord tissues by activating the Nrf2 antioxidant pathway and enhancing the activity of antioxidant enzymes such as SOD and NADPH, forming a "anti-inflammatory-antioxidant" synergistic protective effect. SIRT7 delays neuronal apoptosis by promoting DNA damage repair and inhibiting apoptotic signaling pathways. SIRT3 and SIRT5 target mitochondrial function, improve mitochondrial energy metabolism by regulating the modification status of enzymes involved in the tricarboxylic acid cycle and oxidative phosphorylation, and restore autophagic homeostasis by modulating the acetylation levels of FOXO3a and AMPK, providing metabolic support for neural repair. We summarize that a variety of natural Chinese herbal components (e.g., resveratrol, matrine) and synthetic compounds (e.g., SRT1720, AGK2) can influence the pathological progression of SCI by targeting and regulating members of the Sirtuins family. We propose that Sirtuins-targeted combination therapeutic strategies (e.g., combined with stem cell transplantation, neurotrophic factor supplementation, or antioxidant intervention) are expected to break through the limitations of single therapies and enhance the repair effect of SCI through multi-mechanism synergistic actions. In conclusion, the Sirtuins family exhibits critical mechanisms of action and potential intervention value in the pathophysiological process of SCI. This review summarizes and prospects novel Sirtuins-targeted therapeutic strategies, aiming to provide new insights for basic research and clinical translation in this field.

Abstract:As oncologic therapies continue to advance, the overall survival of cancer patients has markedly increased. Nevertheless, virtually every anticancer treatment modality is accompanied by some degree of cardiotoxicity. Epidemiological data indicate that approximately 30 % of cancer survivors ultimately die from cardiovascular disease. Among the cardiotoxic agents, the anthracycline doxorubicin (DOX) is the most widely used; it effectively suppresses a variety of malignant tumors—including breast cancer, lymphoma, and acute leukemia—but its cardiac toxicity limits further escalation of clinical dosing. Literature reports identify a cumulative dose of ≥250 mg/m2 as the threshold of high risk, with roughly 25 % of patients receiving DOX developing varying degrees of myocardial injury; severe cases progress to heart failure. Even at cumulative doses below the traditional safety limit, some patients exhibit cardiac dysfunction after the first administration, suggesting that cardiotoxicity is not solely a linear function of dose. DOX related cardiotoxicity can be classified as acute (hours to days after administration), sub acute (weeks to months), and chronic/late onset (years later). Most patients initially exhibit only mild reductions in left ventricular ejection fraction (LVEF) or subtle abnormalities in global longitudinal strain (GLS), often without symptoms. Recently, cardiac biomarkers (cTn, NT proBNP) combined with high sensitivity echocardiography (speckle tracking) have been recommended for monitoring high risk individuals, enabling detection of subclinical injury before overt LVEF decline. Currently, several preventive and therapeutic approaches are used in clinical practice, which can be summarized into the following four points: (1) dose limitation and administration strategies: fractionated low dose regimens, liposomal encapsulation, or continuous infusion lower peak plasma concentrations, thereby reducing cardiac exposure; (2) pharmacologic prophylaxis: β blockers (e.g., carvedilol) and ACE inhibitors/ARBs have shown protective effects on LVEF in some randomized trials, though results remain inconsistent and require larger confirmatory studies; (3) metabolic targeted interventions: animal experiments indicate that activation of PPARα or supplementation with L carnitine restores fatty acid oxidation and improves ATP generation, suggesting metabolic modulators as promising cardioprotective candidates; (4) lifestyle modifications: regular aerobic exercise up regulates mitochondrial biogenesis genes (PGC-1α) and reduces reactive oxygen species (ROS) production; small clinical studies have demonstrated a potential benefit in attenuating cTnT elevation. However, DOX-induced cardiotoxicity has not been effectively controlled, indicating that the core mechanism underlying DOX-related cardiac toxicity remains unidentified. Cardiomyocytes are high energy demand cells, and metabolic dysregulation is considered a central component of DOX induced cardiotoxicity. DOX disrupts myocardial metabolic balance through several interrelated pathways. (1) Oxidative stress and mitochondrial damage: DOX generates abundant ROS within cells, leading to mitochondrial membrane potential loss, lipid peroxidation, and iron accumulation, which suppress electron transport chain activity and markedly reduce ATP synthesis efficiency. (2) Autophagy dysregulation: DOX interferes with autophagic flux, preventing the clearance of damaged mitochondria and further aggravating apoptosis and inflammatory responses. (3) Inflammation and cytokine release: oxidative stress activates NF-κB, up-regulating pro inflammatory cytokines such as TNF-α and IL-6, creating a chronic inflammatory microenvironment that weakens myocardial contractility. (4) Epigenetic modifications: studies have shown that DOX alters DNA methylation and histone acetylation patterns in cardiomyocytes, affecting the expression of key metabolic genes (e.g., PGC-1α, CPT-1) and further inhibiting fatty acid β oxidation. These mechanisms collectively lead to suppressed fatty acid oxidation and compensatory up regulation of glycolysis, manifested by an elevated lactate/pyruvate ratio, accumulation of medium chain acyl carnitines, and a pronounced decline in ATP production. The resulting energy deficit precipitates left ventricular contractile dysfunction and, ultimately, heart failure. Despite extensive basic and clinical research on DOX cardiotoxicity, a unified risk assessment model and precise interventions targeting metabolic disturbances remain lacking. This review systematically summarizes recent progress on DOX induced cardiotoxicity and highlights that impairment of myocardial energy metabolism is a central mechanism of injury, thereby deepened our understanding of how impaired myocardial energy metabolism drives DOX induced injury, we can move toward safer chemotherapy protocols that achieve "cure cancer without harming the heart".