Alzheimer's disease (AD) is a complex neurodegenerative condition characterized by metabolic imbalances and neuroinflammation, posing a formidable challenge in medicine due to the lack of effective treatments. Despite considerable research efforts, a cure for AD remains elusive, with current therapies primarily focused on symptom management rather than addressing the disease's underlying causes. This study initially discerned, through Mendelian randomization analysis that elevating pantothenate levels significantly contributes to the prophylaxis of Alzheimer's disease. We explore the therapeutic potential of pantothenate encapsulated in liposomes (Pan@TRF@Liposome NPs), targeting the modulation of CRM1-mediated PKM2 nuclear translocation, a critical mechanism in AD pathology. Additionally, we investigate the synergistic effects of exercise, proposing a combined approach to AD treatment. Exercise-induced metabolic alterations share significant similarities with those associated with dementia, suggesting a potential complementary effect. The Pan@TRF@Liposome NPs exhibit notable biocompatibility, showing no liver or kidney toxicity in vivo, while demonstrating stability and effectiveness in modulating CRM1-mediated PKM2 nuclear translocation, thereby reducing neuroinflammation and neuronal apoptosis. The combined treatment of exercise and Pan@TRF@Liposome NP administration in an AD animal model leads to improved neurofunctional outcomes and cognitive performance. These findings highlight the nanoparticles' role as effective modulators of CRM1-mediated PKM2 nuclear translocation, with significant implications for mitigating neuroinflammation and neuronal apoptosis. Together with exercise, this dual-modality approach could offer new avenues for enhancing cognitive performance and neurofunctional outcomes in AD, marking a promising step forward in developing treatment strategies for this challenging disorder.

Sepsis is a life-threatening condition characterized by complex pathophysiology, including dysregulated immune responses, excessive inflammation, and oxidative stress, often leading to multi-organ failure and high mortality rates. Traditional therapies, such as antibiotics and anti-inflammatory agents, face significant limitations due to issues like drug resistance and inadequate immune modulation. Recent advancements in nanotechnology have introduced innovative solutions by leveraging nanomaterial-based encapsulation systems for bioactive substances, including antioxidants, anti-inflammatory agents, and immunomodulators. These systems enhance the stability, bioavailability, and targeted delivery of therapeutic agents, addressing critical challenges in sepsis management. Key nanocarriers, such as lipid nanoparticles, polymer-based systems, and plant-derived exosomes, offer controlled release mechanisms and precise targeting capabilities, enabling superior therapeutic outcomes. Moreover, nanomaterials' multifunctional properties allow for simultaneous modulation of oxidative stress, inflammation, and immune responses, presenting a synergistic approach to sepsis therapy. However, challenges persist, including the potential toxicity of nanomaterials, scalability of production, and hurdles in clinical translation. This review comprehensively explores the transformative potential of nanotechnology in reshaping sepsis treatment strategies, highlighting its role in advancing precision medicine and its prospects for overcoming current therapeutic barriers.

With an increasing global cancer burden, the regulatory function of the human microbiome and its metabolites in tumor epigenetics has garnered significant interest. Microbial metabolites are not merely passive byproducts but serve as signaling molecules and epigenetic modulators, contributing to tumor progression through multiple overlapping pathways. Short‐chain fatty acids (SCFAs) such as butyrate directly inhibit histone deacetylases to reactivate tumor suppressor genes, while secondary bile acids (BAs) induce gene silencing via DNA methylation remodeling by altering the FXR/TGR5 signaling pathway. Folate and vitamin B12 serve as substrates for DNA and histone methylation through one‐carbon metabolism. A complex bidirectional feedback loop exists between microbial metabolism and tumor epigenetics: reprogramming driven by hypoxia or oncogenes alters metabolite flux, generating molecules such as lactate and succinate that not only remodel chromatin and the tumor microenvironment (TME) but also selectively promote the growth of metabolically adapted microbial species, thereby reinforcing epigenetic dysregulation. Despite growing mechanistic insights, establishing causality and correlating spatiotemporal dynamics and dose responses within the highly heterogeneous TME remain major challenges. Data integration across multi‐omics remains limited by methodological and computational constraints. Resolving these issues will be critical for understanding the microbe–metabolite–epigenetic axis and advancing personalized precision oncology.

The bone–brain axis constitutes an interactive bidirectional signaling network integrating skeletal, neural, and muscular systems, serving critical functions across both normal physiological operations and disease mechanisms. Exercise, a non-pharmacological intervention, significantly influences this axis by enhancing bone-derived factors like osteocalcin, which in turn affect cognitive function, neuroplasticity, and systemic metabolism. This review delves into the molecular and cellular mechanisms underlying the bone–brain axis, with a particular focus on exercise-induced pathways. Physical activity stimulates the secretion of myogenic and neuromodulatory mediators including brain-derived neurotrophic factor (BDNF) and irisin, which augment synaptic adaptability, suppress inflammatory responses, and facilitate neuronal regeneration. These effects are critical in alleviating neurodegenerative diseases, osteoporosis, and mood disorders. The review also examines the endocrine role of bone-derived factors like uncarboxylated osteocalcin and sclerostin in modulating neurotransmitter synthesis and neuroimmune responses, including regulating osteoblast activity and bone remodeling, stimulating BDNF expression in the brain, regulating bone marrow-derived macrophages, and modulating cytokine pathways to alleviate neuroinflammation. Findings suggest that the bone–brain axis not only mitigates age-related degeneration but also holds therapeutic potential for chronic disease management. This review emphasizes the innovative application of exercise in optimizing bone–brain axis functionality, offering critical insights into its capacity to enhance cognitive performance, stabilize affective states, and promote systemic physiological resilience. By elucidating the intricate interplay between skeletal and neurobiological systems, this work paves the way for developing targeted interventions that can improve clinical outcomes in various surgical, orthopedic surgery and neurorehabilitation. Novel insights into the bone–brain axis: exercise-induced endocrine roles in cognitive and mental health: This review synthesizes emerging evidence linking skeletal system signaling to brain function, with a specific focus on the bone–brain axis as a mediator of exercise benefits. By integrating findings from molecular biology, neuroscience, and exercise physiology, we highlight novel endocrine roles of osteokines such as osteocalcin and irisin in promoting cognition and mental health. This interdisciplinary perspective contributes to the growing understanding of exercise as a systemic intervention for neurodegeneration. Learning points : Exercise-induced bone signaling pathways, especially those involving osteocalcin and irisin, support cognitive function, neuroplasticity, and emotional regulation. The bone–brain axis represents a novel and promising therapeutic target for delaying or preventing neurodegenerative diseases. Creatine supplementation combined with exercise demonstrates synergistic potential in promoting both neurological and musculoskeletal health. Emerging interdisciplinary tools, including neuroimaging, artificial intelligence, and gene delivery systems, offer new avenues for personalized exercise-based interventions.

Diabetic wound healing is a significant complication of diabetes mellitus, characterized by prolonged healing times, heightened infection risks, and potential amputations, necessitating innovative therapeutic approaches. This study aims to evaluate the efficacy of a novel injectable hydrogel, AP@HA-Si InjGel, which combines hyaluronic acid, silanol, and bioactive compounds to promote wound healing in diabetic patients. Utilizing a combination of in vitro assays, diabetic mouse models, and advanced techniques such as single-cell RNA sequencing, we demonstrated that AP@HA-Si InjGel significantly accelerates wound closure, enhances collagen deposition, and modulates macrophage polarization towards a pro-healing M2 phenotype while suppressing the inflammatory M1 phenotype. The hydrogel exhibited excellent biocompatibility with over 90 % cell viability and significant antioxidant properties, reducing reactive oxygen species accumulation. Histological analysis confirmed that AP@HA-Si InjGel promoted neovascularization and improved extracellular matrix remodeling, thereby enhancing tissue regeneration. Furthermore, single-cell RNA sequencing revealed distinct macrophage subtypes, with an increased proportion of M2 macrophages and a favorable differentiation trajectory towards enhanced wound healing. Overall, these findings highlight the therapeutic potential of AP@HA-Si InjGel as a comprehensive strategy for diabetic wound management, warranting further exploration in clinical settings to address the growing challenge of impaired wound healing in diabetic patients.

Sepsis is a life‐threatening organ dysfunction caused by a dysregulated host response to infection, in which metabolic reprogramming plays a critical role in disease progression and organ failure. Metabolic reprogramming involves alterations in glucose, lipid, and protein metabolism, leading to imbalanced energy production, immune dysregulation, and tissue damage. Immune cells, under septic stress, switch to aerobic glycolysis, enhancing energy production but causing lactate accumulation and mitochondrial dysfunction, which exacerbates inflammation and organ injury. This metabolic shift emphasizes the need for personalized therapeutic strategies that address the metabolic heterogeneity between pathogens and hosts. The peroxisome proliferator‐activated receptor (PPAR) pathway serves as a central regulator of both metabolic and immune responses, offering protective effects through the promotion of fatty acid oxidation and suppression of inflammation. However, the translational application of PPAR‐directed therapies is constrained by limited drug specificity and significant interpatient heterogeneity. Advances in multiomics technologies provide promising opportunities for identifying metabolic biomarkers and tailoring PPAR‐targeted treatments. Future research should focus on integrating metabolic pathways, developing precise diagnostic tools, and refining personalized interventions to improve sepsis management and patient prognosis. Unlike previous reviews that primarily focus on general immunometabolic alterations in sepsis, this review is the first to systematically integrate PPAR isoform‐specific regulatory mechanisms, multiomics‐based patient stratification, and phenotype‐driven therapeutic targeting, thereby offering a novel framework for precision medicine in sepsis management. We critically evaluate the controversies on the efficacy of PPAR agonists, highlight cross talk with HIF‐1 α /NF‐ κ B/Nrf2, and propose a phenotype‐based stratification for sepsis therapy, a perspective that has not been explored in the literature.