Kunming Medical University, previously known as Kunming Medical College, is a medical school located in Kunming City, Yunnan Province, China.
Traumatic heterotopic ossification (HO) is a debilitating complication of tendon injury, yet its pathogenic mechanisms remain elusive and effective preventive strategies are lacking. Here, we identify a glycometabolic-epigenetic axis that drives HO progression. Single-cell profiling and functional analyses reveal that hypoxic chondrocytes undergo glycolytic reprogramming, leading to lactate accumulation and transfer into tendon-derived mesenchymal stem cells (TD-MSCs) through MCT1. This metabolic coupling promotes P300-dependent histone H3 lysine 18 lactylation (H3K18la), activating osteogenic programs characterized by Col6a1, Zhx3, Lox and Vdr expression and thereby facilitating pathological endochondral ossification. Guided by this mechanism, we develop a tendon-adhesive hydrogel (GelHA-A485@Exos) that integrates mechanical repair with targeted epigenetic modulation. MSC-derived exosomes enable localized delivery of the P300 inhibitor A485, suppressing H3K18la and aberrant osteogenic activation, while the hydrogel scaffold enhances tendon regeneration. In vivo and in vitro studies demonstrate that GelHA-A485@Exos promotes tendon healing while preventing HO formation. Our findings establish metabolic-epigenetic communication as a central regulator of traumatic HO and provide a translational therapeutic strategy for its clinical prevention.
Background Chronic nonhealing wounds remain a considerable challenge in clinical treatment due to excessive inflammation and impeded reepithelialization and angiogenesis. Therefore, the discovery of novel prohealing agents for chronic skin wounds are urgent and important. Amphibian-derived prohealing peptides, especially immunomodulatory peptides, provide a promising strategy for the treatment of chronic skin trauma. However, the mechanism of immunomodulatory peptides accelerating the skin wound healing remains poorly understood. Methods The prohealing ability of peptide Andersonin-W1 (AW1) was assessed by cell scratch, cell proliferation, transwell, and tube formation. Next, full-thickness, deep second-degree burns and diabetic full-thickness skin wounds in mice were performed to detect the therapeutic effects of AW1. Moreover, the tissue regeneration and expression of inflammatory cytokines were evaluated by hematoxylin and eosin (H&E), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry staining. Molecular docking, colocalization, and western blotting were used to explore the mechanism of AW1 in promoting wound healing. Results We provide solid evidence to display excellent prohealing effects of AW1, identified as a short antimicrobial peptide in our previous report. At relative low concentration of nM, AW1 promoted the proliferation, migration, and scratch repair of keratinocyte, macrophage proliferation, and tube formation of HUVEC. AW1 also facilitated reepithelialization, granulation regeneration, and angiogenesis, thus significantly boosting the healing of full-thickness, deep second-degree burns and diabetic skin wounds in mice. Mechanistically, in macrophages, AW1 directly bound to Toll-like receptor 4 (TLR4) in the extracellular region and regulated the downstream nuclear factor‐κB (NF-κB) signaling pathway to facilitate the inflammatory factor secretion and suppress excessive inflammation induced by lipopolysaccharide (LPS). Moreover, AW1 regulated macrophage polarization to promote the transition from the inflammatory to the proliferative phase and then facilitated reepithelialization, granulation regeneration, and angiogenesis, thus exhibiting excellent therapeutic effects on diabetic skin wounds. Conclusions AW1 modulates inflammation and the wound healing process by the TLR4/NF-κB molecular axis, thus facilitating reepithelialization, granulation regeneration, and angiogenesis. These findings not only provided a promising multifunctional prohealing drug candidate for chronic nonhealing skin wounds but also highlighted the unique roles of “small” peptides in the elucidation of “big” human disease mechanisms. Graphical Abstract
Adolescent depression is increasingly prevalent, and the ongoing neurodevelopmental remodeling of the adolescent brain confers heightened vulnerability to stress. Accumulating evidence indicates that stress acts as a primary upstream driver that converges on synaptic dysfunction through tightly interconnected metabolic, inflammatory, and redox pathways. Across prenatal, early-life, and adolescent stress models, stress exposure disrupts synaptic maturation and emotional regulation, with maternal stress and intergenerational effects further amplifying risk during adolescence. At the mechanistic level, stress-induced mitochondrial dysfunction and impaired energy metabolism initiate oxidative imbalance, leading to excessive reactive oxygen species accumulation and weakened antioxidant capacity. These metabolic disturbances synergize with neuroimmune activation—characterized by microglial reactivity, inflammasome signaling, and pro-inflammatory cytokine release—to destabilize synaptic structure and plasticity. Concurrently, dysregulated iron homeostasis exacerbates oxidative damage and ferroptosis-related processes, reinforcing a self-propagating pathological loop that converges on impaired synaptic plasticity, including deficits in long-term potentiation/long-term depression, dendritic spine maintenance, and neurogenesis. Together, these findings support a unified stress–metabolism–inflammation–iron–synapse cascade underlying adolescent depression. Future studies should focus on resolving causal relationships, delineating developmental stage–dependent amplification effects, and integrating multi-omics with clinical evidence to inform early, mechanism-guided interventions and prevention strategies.
Spatial multi-omics technologies are fundamentally shifting breast cancer research from static molecular inventories toward high-resolution spatial atlases of the tumor microenvironment (TME). By integrating spatial transcriptomics, spatial proteomics, and emerging metabolomic approaches, researchers can now map tumor cell heterogeneity, stromal cell subtypes, immune cell topography, and tertiary lymphoid structures (TLSs) within their native tissue context. These spatial insights have enabled the construction of prognostic models based on tumor–immune interface distances, improved prediction of chemotherapy and immunotherapy responses, and facilitated the design of niche‑specific combination therapies targeting, for example, fibroblasts‑rich or immunosuppressive regions. Despite these advances, major challenges remain, including multi‑modal data integration, batch effects, high costs, and the lack of standardized protocols for clinical implementation. Overcoming these bottlenecks is essential to establish “spatial pathology” as a routine tool in precision oncology, ultimately guiding more effective, personalized treatment strategies for breast cancer patients. Importantly, it should be noted that the clinical readiness of spatial features varies substantially: assessment of TLS on routine H E sections is near-implementation, while high-dimensional spatial transcriptomic and proteomic signatures still require standardized protocols, prospective validation, and cost reduction before entering routine diagnostics.
Antibody-drug conjugates (ADCs), generated by covalently linking tumor-targeted monoclonal antibodies to highly potent cytotoxic payloads, have emerged as a pivotal strategy for precision cytotoxic therapy in oncology. Focused on the central theme that technological iteration drives paradigm shifts in cancer treatment, this review systematically summarizes the historical development, clinical applications, current challenges, and future perspectives of ADCs. ADCs have evolved through three generations of technological advances. They have reshaped the treatment landscape across multiple malignancies, advancing from late-line salvage therapy to first-line standard treatment and neoadjuvant settings, and have also begun to show promise in pan-targeted therapy. However, drug resistance and severe adverse events remain key challenges. Next-generation ADC candidates, optimized combination strategies, and the integration of artificial intelligence are being explored to overcome these limitations. ADCs represent a transformative therapeutic modality with demonstrated efficacy across diverse tumor types and treatment lines. While challenges persist, ongoing innovations hold promise for enhancing their clinical utility through precise target selection, optimized payload delivery, and intelligent therapeutic design.
