Atherosclerosis (AS) is a chronic inflammatory disease driven by hypercholesterolemia and characterized by the accumulation of lipid-rich plaques within arterial walls. Although the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) is known to regulate lipid metabolism and inflammation, the precise immunological mechanisms underlying its anti-atherosclerotic effects remain elusive. Here, we investigated the role of PPARα in atherosclerosis using both human and murine models, focusing on its regulation of pathogenic Th17 (pTh17) cell differentiation. Clinical data revealed that PPARα expression in CD4+ T cells significantly decreased with the progression of atherosclerosis. Functionally, PPARα deficiency accelerated plaque formation and instability by selectively promoting pTh17 differentiation, which subsequently impaired macrophage efferocytosis via paracrine crosstalk. Mechanistically, PPARα loss disrupted mitochondrial homeostasis, triggering mitochondrial DNA (mtDNA) leakage and activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-ERK cascade to intrinsically drive pTh17 commitment. Critically, either genetic ablation of STING or pharmacological activation of PPARα reversed these detrimental effects, suppressing pTh17 expansion and restoring macrophage efferocytosis. These findings establish PPARα as a vital metabolic-immune checkpoint, providing a mechanistic rationale for targeting the PPARα-cGAS-STING axis to concurrently attenuate pathogenic T cell inflammation and stabilize atherosclerotic plaques.

As a traditional Chinese medicine, Centella asiatica (CA) contains diverse chemical constituents, which serve as the basis for its broad-spectrum pharmacological activities. This study aimed to investigate the therapeutic effects of CA on glycolipid metabolism disorders in ob/ob mice and conduct a systematic qualitative and quantitative analysis of the chemical composition of CA. The results demonstrated that CA extract effectively ameliorated glucose intolerance and insulin resistance, decreased blood lipid levels, and alleviated hepatic steatosis in ob/ob mice. A total of 39 chemical constituents were identified in the CA extract. To facilitate the quality evaluation of CA, we established a rapid and precise method for the simultaneous quantification of eight target compounds—asiaticoside, asiaticoside B, madecassoside, asiatic acid, madecassic acid, stachyose, kaempferol glucuronide, and quercetin-3- O -glucuronide in CA medicinal materials. Notably, this study represents the first quantitative analysis of stachyose, kaempferol glucuronide, and quercetin-3- O -glucuronide in CA, thereby complementing and expanding the existing framework for its quality control.

Purpose:To elucidate how Salidroside-loaded, oligopeptide-modified tumor exosomes (Salidroside@T-exo) rewire the PI3K/AKT/mTOR axis to remodel the immune microenvironment (IME) and reverse acquired PD-1 resistance in breast cancer. Materials and Methods:CSC-exosomes were surface-engineered with TMTP1 peptide and electroporated with Salidroside. PD-1-resistant MA782/5s-8101-R cells and an orthotopic mouse model were used. Multi-omics, flow cytometry, ELISA, immunofluorescence, in vivo imaging, and molecular assays examined immune and signaling outcomes. Results:Salidroside@T-exo restored T-cell IFN-γ and GZMB secretion, suppressed CD8+ T-cell apoptosis, and inhibited p-PI3K/p-AKT/p-mTOR in T cells. CSC migration, invasion, and stemness (OCT4, NANOG, SOX2) were markedly reduced. Tumor growth, Ki-67 index, and CSC frequency dropped while TUNEL-positive cells rose. Conclusion:Salidroside@T-exo reverses PD-1 blockade resistance by simultaneously inhibiting PI3K/AKT/mTOR signaling in T cells and eradicating breast CSCs, offering a clinically translatable strategy for refractory breast cancer immunotherapy.

Regulatory T cells (Tregs) are essential for maintaining immune balance and limiting inflammatory damage within atherosclerotic plaques. Although the endogenous lipid mediator oleoylethanolamide (OEA) has reported anti-inflammatory and metabolic benefits, its effects on Treg differentiation and function during atherosclerosis are incompletely defined. Here, we tested OEA using in vitro naive CD4+ T-cell polarization assays and in vivo atherosclerosis models. OEA increased CD25+Foxp3+ Treg differentiation in polarization cultures and shifted the Treg compartment in atherosclerotic mice toward a more functional phenotype. PPARα dependence was supported by pharmacologic inhibition with MK886 and by genetic loss of PPARα, both of which abrogated OEA-induced Treg differentiation and functional enhancement. Mechanistically, OEA engaged a PPARα-RORγt pathway consistent with suppression of RORγt-associated programs during Treg differentiation. In therapeutic studies, adoptive transfer of OEA-conditioned Tregs promoted regression of established atherosclerotic plaques. Together, these data identify OEA as a modulator of Treg differentiation and activity and support its potential as a PPARα-dependent strategy to promote plaque regression and immune homeostasis in atherosclerosis.

To develop an atrophic Meibomian Gland Dysfunction (MGD) animal model via liquid nitrogen cryotherapy, the eyelid edges of C57 mice exposure to liquid nitrogen for 30 s. Morphology of MG and ocular surface were assessed using stereomicroscopy and a slit lamp microscope at multiple time points post-injury. Acinar loss and atrophy were observed from day 7, with increased inflammation and apoptosis, and decreased proliferation in acinar cells. Corneal epithelial defects appeared after day 14. Liquid nitrogen induced selective damage to meibomian acinar cells, simulating MGD pathology effectively, with peak effects at day 21, providing a relevant model for atrophic MGD research.

Protein kinases, as one of the most important human enzymes, are signaling molecules that regulate almost all cell activities, including growth, cell division and metabolism. Dysfunction of these cellular pathways can lead to a variety of human diseases. Accumulating evidence on the down-regulation of key protein kinases in diseases has made a big progress. The down-regulation is related to cancer, heart disease, neurodegenerative diseases and other diseases. Thus, in this review, we defined the classifications of protein kinases and demonstrated the mechanisms of protein kinase activators in the treatment of human diseases, summarized the research progress of protein kinase activators, and further discussed the development progress of protein kinase activators in clinical stage. Accordingly, activation of protein kinases has become a crucial target for drug development. With the in-depth understanding of protein kinase functions and regulation mechanisms, the development of new protein kinase activators may continue to be a rapidly growing field, which will help to develop more accurate and effective targeted therapeutic strategies in the near future.

The interaction between infiltrating immune cells and brain-resident cells is critical for inducing an inflammatory response to ischemic stroke. However, the direct effects of CD11b+CD45int microglia in the brain on infiltrating CD11b+CD45highLy6G- monocytes/macrophages (Mos/MΦs) and the precise molecular mechanisms underlying these effects after acute ischemic stroke (AIS) remain unknown. Here, ischemia-induced microglial peroxisome proliferator-activated receptor-alpha (PPARα) downregulation was found to be critical for enhancing the inflammatory response and exacerbating ischemic brain injury by priming peripheral pro-inflammatory Mo/MΦ infiltration. The targeted microglial PPARα signal exerted neuroprotective effects on ischemic stroke by protecting blood-brain barrier (BBB) integrity and inhibiting the infiltration of innate immune cells. Furthermore, overexpression of microglia-specific PPARα exerted neuroprotective effects by enhancing the interleukin (IL)-4 signal-mediated crosstalk of microglia-MΦs. Therefore, our study reveals that ischemia-induced microglial PPARα deficiency expands the inflammatory response and exacerbates ischemic brain injury by enhancing the interaction with infiltrating peripheral Mos/MΦs and suggests that targeting microglial PPARα is a potential therapeutic strategy for improving acute cerebral ischemic injury.

Background:The CHART study established the combination of rezvilutamide and androgen deprivation therapy (ADT) as a standard treatment for patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC). However, the therapeutic outcomes of this regimen in patients with low-volume mHSPC remain insufficiently defined. This study thus aimed to assess the real-world effectiveness of rezvilutamide combined with ADT in the treatment of low-volume mHSPC. Methods:This multicenter, noninterventional, observational study was conducted in China and included adult patients diagnosed with low-volume mHSPC who were treated with rezvilutamide in combination with ADT as determined by the investigator. The study assessed prostate-specific antigen (PSA) responses at multiple time points (3, 6, 9, and 12 months), including a PSA decline ≥50% (PSA50), a PSA decline ≥90% (PSA90), and a PSA level <0.2 ng/mL (undetectable PSA). Subgroup analyses of PSA responses were conducted according to baseline characteristics, including age, Eastern Cooperative Oncology Group performance status (ECOG PS), and Gleason score. Results:Between August 29, 2023 and December 31, 2024, a total of 257 patients were enrolled in the study. The median age was 73 years [interquartile range (IQR), 68-77 years], and the median baseline PSA level was 38 ng/mL (IQR, 7-100 ng/mL). PSA responses were observed as early as 3 months after initiating rezvilutamide treatment, with 88% [176/199; 95% exact confidence interval (CI): 83-93%] achieving PSA50, 75% (149/199; 95% exact CI: 68-81%) achieving PSA90, and 54% (108/199; 95% exact CI: 47-61%) achieving undetectable PSA levels. These responses further improved at subsequent time points (6, 9, and 12 months). By 12 months, 100% (12/12; 95% exact CI: 74-100%) achieved PSA50, 92% (11/12; 95% exact CI: 62-100%) achieved PSA90, and 83% (10/12; 95% exact CI: 52-98%) had undetectable PSA levels. Conclusions:This study is the first to evaluate the effectiveness of rezvilutamide in patients with low-volume mHSPC. In a real-world clinical setting, the combination of rezvilutamide and ADT demonstrated favorable PSA response in this patient population. These findings provide additional treatment options for patients with low-volume mHSPC and support the need for further large-scale research on rezvilutamide in this subgroup.

Time-restricted feeding (TRF) is a dietary intervention that has been shown to have numerous health benefits. However, it is important to further investigate the potential effectiveness of TRF in addressing sarcopenic obesity (SO), which is characterized by a combination of age-related obesity and sarcopenia. In this study, 14-month-old C57BL/6J male mice were fed either regular chow diet or high-fat diet (HFD), and had either ad libitum or restricted access to food for 8 hours daily (Intervention for 7 months). For the human trial (ChiCTR2100052876), obese individuals (n=21) with a Body Mass Index ≥28 were recruited and instructed to adopt an 8-hour eating window and a 16-hour fasting period. Here, we found that the TRF intervention significantly reduced global fat mass (P < .001) and volume (P < .05), and increase lean mass compared to mice fed with HFD. Furthermore, TRF improved overall metabolic mobility (8h TRF+HFD vs. AL+HFD). This intervention also enhanced liver FGF21 protein levels (P < .01) and the expression of FGFR1 and FGF21 target genes in adipose and muscle tissues, thus improving mitochondrial quality control in these tissues. Notably, TRF interventions led to a significant decrease in serum FGF21 levels (P < .05). In the human trial, TRF intervention resulted in a significant reduction in weight (P < .001) and body fat levels (P < .001) among obese individuals, as well as a decrease in serum GLU (P < .001), insulin (P < .001), and TC levels (P < .05). Overall, the findings indicate that TRF intervention improves SO by regulating liver FGF21 expression, thereby enhancing FGF21 sensitivity in adipose and muscle tissues.

Background: Meniere's disease (MD) is a prevalent condition in otolaryngology, with its annual incidence rate increasing. Consequently, understanding the underlying mechanisms of MD is of significant importance. The aim is to investigate the relationship between serum levels of interleukin-1b (IL-1b) and interleukin-18 (IL-18), as well as the activation status of NLRP6 inflammasomes, in patients with Meniere's disease and to evaluate their correlation with the severity of the disease, to improve the treatment strategy of Meniere's disease. Methods: From March 2021 to December 2023, 75 MD patients were selected from the Affiliated Huaian No.1 People's Hospital of Nanjing Medical University for research, and a control group consisting of 75 age-matched healthy individuals was established. Each participant contributed a 5 mL peripheral venous blood sample, which was archived at -80 °C for subsequent analyses. The expression levels of NLRP6 messenger RNA in the blood samples were quantified using real-time fluorescence quantitative PCR methodology. Concentrations of interleukin-1b (IL-1b) and interleukin-18 (IL-18) were measured via enzyme-linked immunosorbent assay (ELISA). Through a comparative examination of NLRP6, IL-1b, and IL-18 levels between MD patients and the healthy controls, the study delved into the potential association between NLRP6 expression and the circulating levels of these two cytokines. In addition, special attention is paid to the differences between unilateral and bilateral MD patients in the above three indexes to evaluate their effectiveness as potential biomarkers for predicting the severity of hearing loss in MD patients. Results: In individuals suffering from MD, a notable elevation was observed in the peripheral blood expression levels of NLRP6, IL-1b, and IL-18 (p<0.001). A correlation assessment disclosed a positive association between the blood NLRP6 content and both IL-1b and IL-18 concentrations among these patients. Notably, no substantial disparity emerged in the expression profiles of these three biomarkers when comparing unilateral versus bilateral MD cases (p>0.05). Furthermore, patients at advanced stages (III+IV) exhibited significantly heightened levels of NLRP6, IL-1b, and IL-18 compared to their counterparts in earlier stages (I+II) (p<0.001). Receiver operating characteristic (ROC) curve analyses demonstrated that the area under the curve (AUC) for NLRP6, IL-1b, and IL-18 stood at 0.8731, 0.8089, and 0.7838, respectively, suggesting their potential as proficient diagnostic markers capable of differentiating MD patients from healthy controls. Conclusions: NLRP6, IL-1b, and IL-18 are highly expressed in the peripheral blood of MD patients. NLRP6, IL-1b, and IL-18 can serve as early diagnostic indicators for MD.

Macrocyclic compounds have emerged as potent tools in the field of drug design, offering unique advantages for enhancing molecular recognition, improving pharmacokinetic properties, and expanding the chemical space accessible to medicinal chemists. This review delves into the evolutionary trajectory of macrocyclic-based strategies, tracing their journey from laboratory innovations to clinical applications. Beginning with an exploration of the defining structural features of macrocycles and their impact on drug-like characteristics, this discussion progresses to highlight key design principles that have facilitated the development of diverse macrocyclic drug candidates. Through a series of illustrative representative case studies from approved macrocyclic drugs and candidates spanning various therapeutic areas, particular emphasis is placed on their efficacy in targeting challenging protein-protein interactions, enzymes, and receptors. Additionally, this review thoroughly examines how macrocycles effectively address critical issues such as metabolic stability, oral bioavailability and selectivity. Valuable insights into optimization strategies employed during both approved and clinical phases underscore successful translation of promising leads into efficacious therapies while providing valuable perspectives on harnessing the full potential of macrocycles in drug discovery and development endeavors.

Hydrogen sulfide (H2S) is a gas signaling molecule with versatile bioactivities; however, its exploitation for disease treatment appears challenging. This study describes the design and characterization of a novel type of H2S donor–drug conjugate (DDC) based on the thio-ProTide scaffold, an evolution of the ProTide strategy successfully used in drug discovery. The new H2S DDCs achieved hepatic co-delivery of H2S and an anti-fibrotic drug candidate named hydronidone, which synergistically attenuated liver injury and resulted in more sufficient intracellular drug exposure. The potent hepatoprotective effects were also attributed to the H2S-mediated multipronged intervention in lipid peroxidation both at the whole cellular and lysosomal levels. Lysosomal H2S accumulation and H2S DDC activation were facilitated by the hydrolysis through the specific lysosomal hydrolase, representing a distinct mechanism for lysosomal targeting independent of the classical basic moieties. These findings provided a novel pattern for the design of optimally therapeutic H2S DDC and organelle-targeting functional molecules.

Long non-coding RNAs (lncRNAs) and Sialic acid-binding immunoglobulin-type lectin (SIGLEC) family members play an important role in proliferation, apoptosis, immune-cell activation and tumor development. However, the relationships of SIGLEC family-related lncRNAs with clinical prognosis and tumor immune microenvironment in ovarian cancer (OC) are still unclear. 426 SIGLEC family-related lncRNAs were obtained according to the screening criteria R > 0.4 and p < 0.05 using Pearson correlation analysis. A risk model contained AL133279.1, AL021878.2, AC078788.1, AC039056.2, AC008750.1 and AC007608.3 was conducted based on the univariate Cox regression analysis, a least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression analyses. OC patient were divided into high-and low-risk group based on the median riskscore. K–M curve and ROC curve revealed that risk model has an abuset prognostic potential for OC patients. Moreover, we successfully validated the prognostic value of the model in the internal datasets, external datasets and clinical sample dataset. Finally, we found that the riskscore was positively correlated with the vast majority of immune cell infiltration. In conclusion, our research identified that a novel SIGLEC family-related lncRNAs risk model to predict the prognosis of OC patients. SIGLEC family-related lncRNAs risk model also has a positive relationship with the tumor immune microenvironment of OC, which may provide a new direction for immunotherapy of OC.

Background LINC00324 is a long-stranded non-coding RNA, which is aberrantly expressed in various cancers and is associated with poor prognosis and clinical features. It involves multiple oncogenic molecular pathways affecting cell proliferation, migration, invasion, and apoptosis. However, the expression, function, and mechanism of LINC00324 in glioma have not been reported. Material and methods We assessed the expression of LINC00324 of LINC00324 in glioma patients based on data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to identify pathways involved in LINC00324-related glioma pathogenesis. Results Based on our findings, we observed differential expression of LINC00324 between tumor and normal tissues in glioma patients. Our analysis of overall survival (OS) and disease-specific survival (DSS) indicated that glioma patients with high LINC00324 expression had a poorer prognosis compared to those with low LINC00324 expression. By integrating clinical data and genetic signatures from TCGA patients, we developed a nomogram to predict OS and DSS in glioma patients. Gene set enrichment analysis (GSEA) revealed that several pathways, including JAK/STAT3 signaling, epithelial-mesenchymal transition, STAT5 signaling, NF-κB activation, and apoptosis, were differentially enriched in glioma samples with high LINC00324 expression. Furthermore, we observed significant correlations between LINC00324 expression, immune infiltration levels, and expression of immune checkpoint-related genes (HAVCR2: r = 0.627, P = 1.54e-77; CD40: r = 0.604, P = 1.36e-70; ITGB2: r = 0.612, P = 6.33e-7; CX3CL1: r = -0.307, P = 9.24e-17). These findings highlight the potential significance of LINC00324 in glioma progression and suggest avenues for further research and potential therapeutic targets. Conclusion Indeed, our results confirm that the LINC00324 signature holds promise as a prognostic predictor in glioma patients. This finding opens up new possibilities for understanding the disease and may offer valuable insights for the development of targeted therapies.

BackgroundDelivery systems based on albumin nanoparticles (NPs) have recently garnered substantial interest in anti-tumor drug development. However, systematic bibliometric analyses in this field remain lacking. This study aimed to analyze the current research status, hotspots, and frontiers in the application of albumin NPs in the field of oncology from a bibliometric perspective.MethodsUsing the Web of Science Core Collection (WOSCC) as the data source, retrieved articles were analyzed using software, such as VOSviewer 1.6.18 and CiteSpace 6.1.6, and the relevant visualization maps were plotted.ResultsFrom 1 January 2000, to 15 April 2024, 2,262 institutions from 67 countries/regions published 1,624 articles related to the application of albumin NPs in the field of oncology. The USA was a leader in this field and held a formidable academic reputation. The most productive institution was the Chinese Academy of Sciences. The most productive author was Youn YS, whereas Kratz F was the most frequently co-cited author. The most productive journal was the International Journal of Nanomedicine, whereas the Journal of Controlled Release was the most co-cited journal. Future research hotspots and frontiers included “rapid and convenient synthesis methods predominated by self-assembly,” “surface modification,” “construction of multifunctional NPs for theranostics,” “research on natural active ingredients mainly based on phenolic compounds,” “combination therapy,” and “clinical applications.”ConclusionBased on our bibliometric analysis and summary, we obtained an overview of the research on albumin NPs in the field of oncology, identified the most influential countries, institutions, authors, journals, and citations, and discussed the current research hotspots and frontiers in this field. Our study may serve as an important reference for future research in this field.

Regulated cell death (RCD) is a controlled form of cell death orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, and modulating immunity. Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival. Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse, comparable to apoptosis. Moreover, they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs. With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines, a growing number of small-molecule compounds targeting single or multiple pathways have been discovered, providing novel strategies for current cancer therapy. In this review, we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines, mainly including autophagy-dependent cell death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic cell death, NETotic cell death, lysosome-dependent cell death, and immunogenic cell death (ICD). Furthermore, we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds. In brief, these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines, ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics.

Both bone and cartilage microenvironments play a crucial role in the regeneration of osteochondral defects caused by osteoarthritis (OA). A major challenge is how to simulate gradient changing mechanical properties and inducing abilities of regenerative microenvironments on the integrated scaffold to achieve simultaneous regeneration. In this work, a concept of biphasic ECM assembled graphene oxide-collagen (GO-COL)/ Nano-hydroxyapatite (nHap) composite is proposed. GO-COL/nHap bilayer scaffold with gradient concentration was formed by crosslinking and freeze-drying in stages to mimic the gradient distribution of mechanical properties of articular cartilage and bone. Then we prepared chondrogenic/osteogenic ECM membranes (CgECM/OgECM) with chondrocytes from rat knee respectively, and assembled them onto corresponding layers. The morphology, physical properties, biocompatibility, and osteochondrogenic capability of the scaffold were evaluated in vitro and in vivo. Mechanically, gene expression and protein level assessments showed greater osteochondrogenic activity in the biphasic ECM scaffold group compared to the GO-COL bilayer scaffold group. In vivo studies using a rat knee osteochondral defect model further confirmed the superior repair effect of the biphasic ECM-scaffold group compared to the blank group. Taken together, the proposed ECM assembled GO-COL/nHap strategy open a window to realize different microenvironment mimicking in a whole scaffold, making it a potential off-the-shelf method for osteochondral tissue engineering.

Background: Long noncoding RNAs (lncRNAs) are reported that play an important role in regulating tumorigenesis. This study aims to develop a ferroptosis-related lncRNA gene signature for predicting biochemical recurrence of prostate cancer (PCa) and prove a functional lncRNA BCRP3 as a promotor toward PCa progression.Methods: The ferroptosis-related lncRNA were identified by interoperating the databases of The Cancer Genome Atlas (TCGA) and FerrDb. A predictive model for biochemical recurrence of PCa was established based on the LASSO Cox regression. Kaplan-Meier cures were applied in the measurement of the impact on patients' survival caused by key lncRNAs. Meanwhile, the molecular assays of CCK8, EdU, wound healing, and Transwell were conducted to evaluate the tumor-suppressive effect of BCRP3 in vitro.Results: This study presented that 17 differentially expressed ferroptosis-related lncRNAs were confirmed and further screened out 9 key lncRNAs for the establishment of risk model. The nomogram involved the risk model was also proved with an excellent predictive performance toward 1-, 3-, and 5-year survival with the area of curves (AUC) as 0.77, 0.79, and 0.65 separately. Notably, the lncRNA BCRP3 was significantly correlated with the survival of PCa patients based on multivariate Cox regression. Additionally, downregulation of BCRP3 effectively inhibited the proliferation, migration, and invasion of PC3 cells which further proved its anti-tumor function.Conclusion: We developed a ferroptosis-related lncRNA risk model for predicting biochemical recurrence, which assisting in the clinical therapy of patients with PCa.

The microenvironment mediated by the microglia (MG) M1/M2 phenotypic switch plays a decisive role in the neuronal fate and cognitive function of Alzheimer's disease (AD). However, the impact of metabolic reprogramming on microglial polarization and its underlying mechanism remains elusive. This study reveals that cordycepin improved cognitive function and memory in APP/PS1 mice, as well as attenuated neuronal damage by triggering MG-M2 polarization and metabolic reprogramming characterized by increased OXPHOS and glycolysis, rather than directly protecting neurons. Simultaneously, cordycepin partially alleviates mitochondrial damage in microglia induced by inhibitors of OXPHOS and glycolysis, further promoting MG-M2 transformation and increasing neuronal survival. Through confirmation of cordycepin distribution in the microglial mitochondria via mitochondrial isolation followed by HPLC-MS/MS techniques, HKII and PDK2 are further identified as potential targets of cordycepin. By investigating the effects of HKII and PDK2 inhibitors, the mechanism through which cordycepin targeted HKII to elevate ECAR levels in the glycolysis pathway while targeting PDK2 to enhance OCR levels in PDH-mediated OXPHOS pathway, thereby inducing MG-M2 polarization, promoting neuronal survival and exerting an anti-AD role is elucidated.