Wound healing remains a critical global healthcare challenge, with an annual treatment cost exceeding $50 billion worldwide. Over the past decade, significant advances in wound care have focused on developing sophisticated biomaterials that promote tissue regeneration and prevent complications. Despite these developments, there remains a crucial need for multifunctional wound healing materials that can effectively address the complex, multiphase nature of wound repair while being cost effective and easily applicable in various clinical settings. This review systematically analyzes the latest developments in wound healing materials, examining their chemical composition, structural design, and therapeutic mechanisms. We comprehensively evaluate various bioactive components, including natural polymers, synthetic matrices, and hybrid composites, along with their different forms, such as hydrogels, powders, and smart dressings. Special attention is given to emerging strategies in material design that integrate multiple therapeutic functions, including sustained drug delivery, infection prevention, and tissue regeneration promotion. The insights provided in this review illuminate the path toward next-generation wound healing materials, highlighting opportunities for developing more effective therapeutic solutions that can significantly improve patient outcomes and reduce healthcare burden.

The lack of natural aging-inducing Alzheimer's disease (AD) model presents a significant gap in the current preclinical research. Here, we identified a unique cohort of 10 naturally aging tree shrews (TSs) displaying distinct Alzheimer's-like pathology (ALP) from a population of 324, thereby establishing a novel model that closely mirrors human AD progression. Using single-nucleus RNA sequencing, we generated a comprehensive transcriptome atlas, revealing the cellular diversity and gene expression changes underlying AD pathology in aged TSs. Particularly, distinct differentiation trajectories of neural progenitor cells were highly associated with AD pathology. Intriguingly, cross-species comparisons among humans, TSs, monkeys, and mice highlighted a greater cellular homogeneity of TSs to primates and humans than to mice. Our extended cross-species analysis by including a direct comparison between human and TS hippocampal tissue under AD conditions uncovered conserved cell types, enriched synaptic biological processes, and elevated excitatory/inhibitory imbalance across species. Cell–cell communication analysis unveiled parallel patterns between AD human and ALP TSs, with both showing reduced interaction strength and quantity across most cell types. Overall, our study provides rich, high-resolution resources on the cellular and molecular landscape of the ALP TS hippocampus, reinforcing the utility of TSs as a robust model for AD research.

Anoikis resistance in hepatocellular carcinoma (HCC) cells boosts survival and metastasis. This study aimed to establish an anoikis-related genes (ARGs)-based model for predicting HCC patients’ outcomes and investigate the clinicopathological significance and function of crucial ARGs. The transcriptional expression patterns for HCC cohorts were compiled from TCGA, GEO and ICGC. Univariate and LASSO multivariate analyses were performed to screen for prognostic ARGs. Gain- and loss-of-function studies, RNA sequencing, and mass spectrometry were employed to elucidate the underlying mechanisms of ARGs in HCC. We established a five-gene ARGs risk model for HCC prognosis, with an AUC value of 0.812 for 1-year survival. Among the five genes, Rac family small GTPase 3 (RAC3) was upregulated in HCC relative to adjacent normal tissues and negatively correlated to overall survival and disease-free survival of patients with HCC. Silence of RAC3 in HCC cells resulted in an increased cell apoptosis and diminished cell proliferation and invasion. Mechanistically, we uncovered that RAC3 binding with SOX6 propelled the advancement of HCC cells through NNMT-mediated stimulation of the cAMP/MAPK/Rap1 signaling. In particular, EHop-016, a small molecule inhibitor targeting RAC3, significantly suppressed HCC progression.

In recent years, proteolysis targeting chimera (PROTAC) technology has made significant progress in the field of drug development. Traditional drugs mainly focus on inhibiting or activating specific proteins, while PROTAC technology provides new ideas for treating various diseases by inducing the degradation of target proteins. Especially for peptide PROTACs, due to their unique structural and functional characteristics, they have become a hot research topic. This review provides a detailed description of the key components, mechanisms, and design principles of peptide PROTACs, elaborates on their applications in skin-related diseases, oncology, and other potential therapeutic fields, analyzes their advantages and challenges, and looks forward to their future development prospects. The development of peptide PROTAC technology not only opens up new paths for drug research and development, but also provides new ideas for solving the resistance and safety issues faced by traditional small-molecule drugs. Compared with small-molecule PROTACs, peptide PROTACs have advantages such as multitargeting, biodegradability, low toxicity, and flexibility in structural design. With the deepening of research and the continuous maturity of technology, peptide PROTACs are expected to become one of the important strategies for future drug discovery, providing new hope for the treatment of more intractable diseases. Peptide PROTACs are ushering in a new era of precision medicine.

Abnormal lipid metabolism in microglia leads to the formation of pathological lipid droplets (LDs), a phenomenon also observed in neurodegenerative diseases such as Alzheimer's disease (AD). The abnormal accumulation of LDs disrupts normal cellular function and exacerbates the pathological process of AD. ATP11B is a P4-ATPase and the expression of Atp11b changes in the brain of patients with AD and diseases of lipid metabolism. The present study aimed to explore the regulatory role of ATP11B in microglial lipid metabolism and assess the potential of ATP11B as a therapeutic target for AD. Atp11b deficiency caused excessive fatty acid uptake and activated the PPAR signaling pathway, resulting in abnormal synthesis of neutral lipids and mitochondrial energy metabolism in microglia. Further results showed that Atp11b deficiency led to the accumulation of pathological LDs in microglia and AD mice. Conversely, overexpression of Atp11b alleviated exploratory behavior impairment, learning and memory impairment, LD accumulation, beta-amyloid (Aβ) deposition, and inflammatory response in the brain of AD mice. These findings provide important clues for a better understanding of the pathogenesis of AD and for developing novel therapeutic strategies.

Phosphatidylserine (PS) exposes to the outer plasma membrane after a pathological insult (e.g., stroke) but not under normal conditions whereby PS remains within the inner plasma membrane. However, the reversibility and translational potential of PS exposure in damaged cells after stroke are still unknown. Here, we demonstrated that plasma Annexin V, which has a high affinity to membranes bearing PS, was increased in patients with salvage penumbra after endovascular therapy, and associated with early neurological improvement. Moreover, Annexin V treatment could decrease PS exposure and mitigate neurological impairments in transient ischemia/reperfusion mouse models, but not in permanent ischemia. Furthermore, we used a combination of cell, rodent, and nonhuman primate ischemia/reperfusion models and found that transmembrane protein 30A (Tmem30a) was increased in the ischemic penumbra after stroke and imperative for less PS exposure and better neurological functions. Mechanistically, mitigation of PS exposure mediated by Tmem30a/Annexin V connection led to decreased expression of apoptosis and necroptosis markers in neurons of penumbra. Overall, our findings reveal a previously unappreciated role of reducing PS exposure by Annexin V treatment in protecting the penumbra in a clinically relevant ischemia/reperfusion model. Tmem30a is essential for reducing PS exposure in the penumbra after ischemic stroke.

Postoperative delirium (POD) is a common postsurgical complication that seriously affects patients' prognosis and imposes a heavy burden on families and society. Type 2 diabetes mellitus (T2DM) is a major risk factor for POD. The susceptibility mechanisms of POD in T2DM individuals and the role of exercise preconditioning remain unclear. Adult rats with and without T2DM were used to assess the promotive effect of diabetes on postoperative delirium-like behavior. The diabetic rats were also subjected to a swimming exercise program before surgery. The potential beneficial effect of exercise preconditioning on postoperative cognition was evaluated by examining neurobehavior, hippocampal neuroinflammation, mitochondrial morphology, and function in diabetic rats. Finally, underlying mechanisms were further analyzed by exploring the role of the sirtuin family in vivo and in vitro. We found that performing tibial fracture surgery resulted in delirium-like behavior and inhibited hippocampal mitochondrial biogenesis in diabetic rats but not in healthy rats. Preoperative swimming exercise was beneficial in attenuating delirium-like behavior, inhibiting neuroinflammation, and improving mitochondrial biogenesis and function. Preoperative swimming exercise achieved these positive effects by upregulating SIRT2-mediated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) deacetylation and activating mitochondrial biogenesis in T2DM rats.

Currently, there is little evidence supporting the use of early endpoints to assess primary treatment outcomes in nasopharyngeal carcinoma (NPC). We aim to explore the relationship between 24-month progression-free survival (PFS24) and subsequent overall survival (sOS) as well as loss of lifetime (LoL) in NPC patients. sOS is defined as survival from the 24-month point or progression within 24 months leading to mortality. LoL represents the reduction in life expectancy due to NPC, compared to the general population matched by age, sex, and calendar year. The standardized mortality ratio (SMR) is defined as the ratio of observed mortality to expected mortality. The study included 6315 patients from nonendemic and endemic regions of China. Among them, 5301 patients (83.9%) achieved PFS24, with a 5-year sOS of 90.2% and an SMR of 1.0. Over a 10-year period following treatment, the mean LoL was only 0.01 months/year. For most subgroups, patients achieving PFS24 exhibited comparable sOS and LoL with the general population. However, patients failing to achieve PFS24 showed significantly worse outcomes, with 5-year sOS of 21.9%, SMR of 23.7, and LoL of 6.48 months/year. These notable outcome disparities highlight the importance of PFS24 in NPC risk stratification, patient monitoring, and study design.

In tauopathies, defects in autophagy-lysosomal protein degradation are thought to contribute to the abnormal accumulation of aggregated tau. Recent studies have shown that (−)-Epicatechin (Epi), a dietary flavonoid belonging to the flavan-3-ol subgroup, improves blood flow, modulates metabolic profiles, and prevents oxidative damage. However, less research has explored the effects of Epi on tauopathies. Here, we found that Epi rescued cognitive deficits in P301S tau transgenic mice, a model exhibiting characteristics of tauopathies like frontotemporal dementia and Alzheimer's disease, and attenuated tau pathology through autophagy activation. Proteomic and biochemical analyses revealed that P301S mice exhibit deficits in autophagosome formation via modulating mTOR, consequently inhibiting autophagy. Epi inhibited the mTOR signaling pathway to promote autophagosome formation, which is essential for the clearance of tau aggregation. By using chloroquine (CQ) to inhibit autophagy in vivo, we further confirmed that Epi induced tau degradation via the autophagy pathway. Lastly, Epi administration was also found to improve cognition by reversing spine decrease and neuron loss, as well as attenuating neuroinflammation. Our findings suggest that Epi promoted tau clearance by activating autophagy, indicating its potential as a promising therapeutic candidate for tauopathies.

Respiratory syncytial virus (RSV) causes severe acute lower respiratory tract infections, especially in infants and the elderly. Developing an RSV vaccine that promotes a robust mucosal immune response is necessary to successfully prevent viral transmission and the development of severe disease. We previously reported that crosslinked carbon dots (CCD) may be an excellent adjuvant candidate for intranasal (IN) protein subunit vaccines. Considering the strong immunogenicity of RSV prefused F protein (preF), we prepared an IN RSV vaccine composed of the CCD adjuvant and the preF protein as antigen (CCD/preF) and evaluated the induced antigen-specific humoral and cellular immunity. We found that IN immunization with the CCD/preF vaccine elicited strong serum IgG responses and mucosal immunity, including secreted IgA antibodies, tissue-resident memory T (T_RM) cells, and antigen-specific B cells, which lasted for at least 1 year. In addition, a combination of intramuscular and IN immunization with CCD/preF vaccine induced stronger systemic and mucosal immunity. Together, this study proved the high immunogenicity of the CCD/preF vaccines and supported the university of the mucosal CCD adjuvant, supporting further development of the CCD/preF vaccine in larger animal models and clinical studies.

Triple-negative breast cancer (TNBC) remains a challenge due to its aggressive nature and limited therapeutic options. Calpain 2, a member of the calcium-dependent cysteine protease family, is particularly associated with poor prognosis in TNBC. This study explores the isoform-specific role of calpain 2 in TNBC, examining its correlation with prognosis and its mechanistic impact on metastasis. Bioinformatic analyses, including Kaplan–Meier survival plots, univariate Cox proportional analysis, and gene set enrichment analysis (GSEA), assessed CAPN2 expression and its association with mesenchymal genes in TNBC. Results of cell-based experiments with CAPN2 knockdown or overexpression indicate that elevated CAPN2 expression correlates with poor clinical outcomes and enhanced metastatic potential in TNBC. CAPN2 knockdown inhibited the epithelial–mesenchymal transition (EMT), reducing cancer cell proliferation, migration, and invasion. Calpain 2 downregulation reversed the EMT by reducing isoform-specific cleavage of filamin A, HIF1α nuclear localization and TWIST1 transcription. CNa 29, a calpain 2-specific inhibitor, reduced cancer cell proliferation, decreased filamin A cleavage, downregulated TWIST1 expression, and significantly retarded metastasis,. In conclusion, calpain 2 plays a critical role in TNBC progression by modulating HIF1α and TWIST1, to promote the EMT and metastasis. Isoform-selective inhibition of calpain 2 with CNa 29 presents a promising therapeutic strategy for managing TNBC.

Transforming growth factor beta2 (TGFβ2) is upregulated in gastric cancer (GC), playing a crucial role in driving its progression. However, the biological effects of TGFβ2 in GC metastasis and proliferation remain not fully understood. Our study reveals that TGFβ2 enhances N-myc downstream-regulated gene 1 (NDRG1) protein expression by activating the TGFβR/Smad2/3-dependent pathway, accelerating GC progression. TGFβ2 knockdown downregulates NDRG1 by inhibiting the TGFβR/Smad2/3 signaling pathway, which in turn inhibits GC cell migration and epithelial–mesenchymal transition (EMT) but stimulates proliferation. Both TGFβ2 upregulation and NDRG1 upregulation enhance GC cell migration in vitro and promote lung metastasis in mouse models. Interfering with NDRG1 reverses TGFβ2-induced migration, and inhibiting Smad2/3 or TGFβR reverses TGFβ2-induced NDRG1 upregulation and GC cell migration. Clinical sample analysis shows high TGFβ2 and NDRG1 expression in GC, associated with poor prognosis. Our study reveals that TGFβ2 upregulates NDRG1 via the TGFβR/Smad2/3 pathway, driving GC progression and highlighting the potential role of the TGFβ2NDRG1 axis in GC-targeted therapies.

Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor involved in multiple physiological and pathological processes. While STAT3 plays an essential role in homeostasis, its persistent activation has been implicated in the pathogenesis of various diseases, particularly cancer, bone-related diseases, autoimmune disorders, inflammatory diseases, cardiovascular diseases, and neurodegenerative conditions. The interleukin-6/Janus kinase (JAK)/STAT3 signaling axis is central to STAT3 activation, influencing tumor microenvironment remodeling, angiogenesis, immune evasion, and therapy resistance. Despite extensive research, the precise mechanisms underlying dysregulated STAT3 signaling in disease progression remain incompletely understood, and no United States Food and Drug Administration (USFDA)-approved direct STAT3 inhibitors currently exist. This review provides a comprehensive evaluation of STAT3's role in health and disease, emphasizing its involvement in cancer stem cell maintenance, metastasis, inflammation, and drug resistance. We systematically discuss therapeutic strategies, including JAK inhibitors (tofacitinib, ruxolitinib), Src Homology 2 domain inhibitors (S3I-201, STATTIC), antisense oligonucleotides (AZD9150), and nanomedicine-based drug delivery systems, which enhance specificity and bioavailability while reducing toxicity. By integrating molecular mechanisms, disease pathology, and emerging therapeutic interventions, this review fills a critical knowledge gap in STAT3-targeted therapy. Our insights into STAT3 signaling crosstalk, epigenetic regulation, and resistance mechanisms offer a foundation for developing next-generation STAT3 inhibitors with greater clinical efficacy and translational potential.

ALK fusions, such as the classic EML4-ALK, are known drivers of lung cancer and effective therapeutic targets. However, variant ALK fusions, including intergenic fusions like LOC388942-ALK (LA), have been detected in increasing numbers of patients, with their roles in tumorigenesis and ALK inhibitor resistance remaining unclear. Using CRISPR/Cas9, we generated the LA fusion in A549 and H441 cells, confirming elevated ALK expression via qRT-PCR and immunohistochemistry (IHC) staining. Functional analyses showed that LA significantly promoted tumor growth in vitro and in vivo while conferring increased resistance to alectinib. RNA-seq revealed upregulation of the FOS pathway in LA tumors, identifying FOS as a potential therapeutic target. Subsequently, we demonstrated that FOS disruption and inhibition sensitized LA tumors to treatment. RNA-seq profiling demonstrated that FOS depletion in LOC388942-ALK tumor significantly downregulated multiple oncogenic pathways related to cell cycle progression, DNA replication fidelity, and extracellular matrix remodeling, suggesting a pivotal role of FOS in maintaining tumor growth. These findings establish LOC388942-ALK as a novel oncogenic driver in lung cancer, highlighting its role in tumor growth and ALK inhibitor resistance. Targeting FOS may provide a promising therapeutic strategy for tumors harboring this intergenic fusion.

Bone is responsible for providing mechanical protection, attachment sites for muscles, hematopoiesis micssroenvironment, and maintaining balance between calcium and phosphorate. As a highly active and dynamically regulated organ, the balance between formation and resorption of bone is crucial in bone development, damaged bone repair, and mineral homeostasis, while dysregulation in bone remodeling impairs bone structure and strength, leading to deficiency in bone function and skeletal disorder, such as osteoporosis. Osteoporosis refers to compromised bone mass and higher susceptibility of fracture, resulting from several risk factors deteriorating the balanced system between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. This balanced system is strictly regulated by translational modification, such as phosphorylation, methylation, acetylation, ubiquitination, sumoylation, glycosylation, ADP-ribosylation, S-palmitoylation, citrullination, and so on. This review specifically describes the updating researches concerning bone formation and bone resorption mediated by posttranslational modification. We highlight dysregulated posttranslational modification in osteoblast and osteoclast differentiation. We also emphasize involvement of posttranslational modification in osteoporosis development, so as to elucidate the underlying molecular basis of osteoporosis. Then, we point out translational potential of PTMs as therapeutic targets. This review will deepen our understanding between posttranslational modification and osteoporosis, and identify novel targets for clinical treatment and identify future directions.

Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS–MAPK, PI3K–AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody–drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.

Tuberculous pleural effusion (TPE) is a prevalent form of extrapulmonary tuberculosis, and immune abnormalities play a crucial role in promoting its development. However, the dynamic changes and regulatory characteristics of immune cells during TPE progression remain incompletely understood. This study analyzed DNA methylation and transcriptome data from macrophages and CD4⁺ T cells from pleural lavage fluid of BCG-induced tuberculous pleurisy mouse models at specific time points (Days 0, 1, 7, and 14). The results revealed substantial alterations in DNA methylation patterns associated with inflammatory factors and interferon genes. Notably, macrophages exhibited the most pronounced differences in DNA methylation profiles on Day 1, while CD4⁺ T cells demonstrated gradual changes over time. The investigation further indicated that DNA methylation primarily regulated the differentiation of Th1, Th17, and Th22 cells but not Th9 cells. Additionally, single-cell RNA sequencing analysis revealed an increasing expression of C1q during infection, which was regulated by DNA methylation. Importantly, C1q⁺ and C1q⁻ macrophages demonstrated distinct roles in modulating immune responses during infection. This research provides valuable insights into the DNA methylation profile of immune cells during Mycobacterium bovis infection–induced pleurisy in a mouse model, enhancing our understanding of the upstream regulatory mechanisms underlying immune response development in TPE.

It remains undetermined regarding the impact of neoadjuvant therapy on immunogenic cell death (ICD) and subsequent tumor microenvironment (TME) remodeling in esophageal squamous cell carcinoma (ESCC). And it is of paramount significance to identify beneficiaries from neoadjuvant therapy in treatment-naïve ESCC. In this study, 88 ESCC samples undergoing neoadjuvant therapy plus surgery (NA+S) or surgery alone (SA) were subjected to bulk-RNA sequencing. A five-gene RINscore incorporating ICD-related signature genes with TME-based hub genes was established to predict clinical outcomes and pharmacological responses, in which SLAMF7 and IL1R1 were selected out as co-expressed genes. The regulatory mechanism of the repressive co-transcription factor BATF of SLAMF7 and IL1R1 was further demonstrated. Our data demonstrated that NA+S led to high abundance in kinds of T helper cells, nature killer T cells and M1-like macrophages with increased CD8+T cells infiltration compared with SA. ICD phenotypes were further characterized in treatment-naïve ESCC to determine their differences in TME and potential benefits from NA. Our findings not only offered novel insights into the distinct TME and ICD profiles of ESCC undergoing different therapeutic modes, but also provided the RINscore, which may aid oncologists in determining individualized (neo)adjuvant immunotherapy regimen.