Yuntian Shen

Background: Skeletal muscle atrophy is a pathological condition characterized by a progressive loss of muscle mass and function. Its core mechanisms involve an imbalance between protein synthesis and degradation, caused by oxidative stress and inflammation. Tectorigenin (TG) shows therapeutic potential but suffers from poor solubility and bioavailability. This study developed a zeolitic imidazolate framework‐8 (ZIF‐8) nanocarrier for TG (ZIF‐8@TG) to enhance delivery efficacy against neurogenic muscle atrophy. Methods: ZIF‐8@TG nanoparticles were synthesized and characterized for size, drug loading, release profile and cytotoxicity. Their therapeutic effects were investigated in vitro using a nutrient deprivation‐induced C2C12 myotube atrophy model and in vivo using a sciatic nerve crush injury–induced mouse model of muscle atrophy. Immunofluorescence staining and western blotting were performed to assess the effects of ZIF‐8@TG on atrophic myotubes. Behavioural tests, immunofluorescence staining and western blotting were used to evaluate its impact on muscle atrophy in vivo. The underlying mechanisms were further explored through western blotting, electron microscopy, immunofluorescence staining and H&E staining. Results: ZIF‐8@TG nanoparticles (approx. 50 nm) exhibited pH‐responsive release and efficient cellular uptake. In vitro, nutrient deprivation reduced myotube diameter by 53% ( p < 0.01), whereas ZIF‐8@TG treatment restored it to 92% of control levels, showing significantly better efficacy than free TG. In vivo, sciatic nerve injury decreased tibialis anterior muscle mass by 35% ( p < 0.001) and mean myofiber cross‐sectional area (CSA) by 41% ( p < 0.001). ZIF‐8@TG treatment significantly increased muscle mass to 74% and CSA to 93% of control values, whereas free TG resulted in non‐significant improvements. Additionally, ZIF‐8@TG improved motor function in mice following sciatic nerve crush. Mechanistically, the alleviation of skeletal muscle atrophy by ZIF‐8@TG may be associated with regulation of excessive activation of the ubiquitin‐proteasome system and autophagy‐associated changes, along with enhanced protein synthesis–related Akt/mTOR signalling pathway during sciatic nerve crush–induced muscle atrophy, as well as an association with reduced oxidative stress and inflammation. Conclusions: ZIF‐8@TG effectively delivers TG, alleviating muscle atrophy in vitro and in vivo. ZIF‐8@TG treatment is associated with reduced oxidative stress and inflammation, preserved protein homeostasis and improved functional recovery, offering a promising nanotechnology‐based therapy strategy for neurogenic skeletal muscle atrophy.

Introduction: Epilepsy is a complex neurological disorder characterized by recurrent seizures. A substantial proportion of patients develop drug‐resistant epilepsy (DRE), highlighting the limitations of current therapies and the need to view epilepsy beyond the traditional “channelopathy” hypothesis as a multifactorial network disorder. Method: This narrative review synthesizes current evidence on epilepsy pathogenesis, mechanisms of drug resistance, and emerging therapeutic strategies. Relevant studies were identified through literature searches of PubMed and Web of Science, with emphasis on publications from 2018 to 2025 and landmark studies that have shaped current understanding of epileptogenesis, drug‐resistant epilepsy, and precision therapy. Results: The pathogenesis of epilepsy converges genetic, neuroinflammatory, and cellular homeostasis pathways. Key drivers include ion channel mutations, glia‐mediated neuroinflammation, and dysregulated processes like autophagy and ferroptosis. These contribute to drug resistance and comorbidities, driving a therapeutic shift toward precision and network‐modulation strategies, such as gene therapy, targeted pathway modulation, and neuromodulation, with the ultimate goal of achieving disease modification rather than seizure suppression alone. Conclusions: Integrating multi‐omics insights to construct a holistic precision medicine framework, spanning from molecular diagnosis to tailored network therapy, is fundamental for advancing epilepsy treatment. Future efforts must focus on translating this integrated understanding into effective clinical strategies to overcome therapeutic resistance.

Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the lung cancer tumor microenvironment (TME), where their functions vary according to developmental origin, local signals, metabolic conditions, spatial location, and treatment exposure. The conventional M1 and M2 framework therefore does not adequately represent the diversity of macrophage states in human tumors. This narrative review examines the origin of TAMs in lung cancer, their context-dependent functional states, spatial organization, and interactions with current treatments in non-small cell lung cancer and small cell lung cancer. Single-cell RNA sequencing and spatial transcriptomics have identified macrophage populations associated with primary tumors and specific metastatic sites. Mechanistic studies further implicate cytokine signalling, extracellular vesicle communication, metabolic regulation, and phagocytosis checkpoints in tumor cell proliferation, stemness maintenance, epithelial-mesenchymal transition (EMT), angiogenesis and the formation of an immunosuppressive microenvironment. TAMs can contribute to tumor clearance in some settings but promote immune suppression, tissue repair, and treatment resistance in others. Targeting strategies directed against TAMs, including inhibition of monocyte recruitment, modification of tumor-supportive macrophage states, blockade of phagocytosis checkpoints, and macrophage-directed drug delivery, have demonstrated activity primarily in experimental lung cancer models. However, clinical studies have not yet established the efficacy, selectivity, or safety of these approaches. Major challenges remain, including the high heterogeneity of TAMs, activation of compensatory pathways, systemic toxicity, and the translational gap between preclinical and clinical studies. Future research should focus on validating markers that distinguish disease-associated macrophage states from macrophages required for pulmonary homeostasis and integrating longitudinal tissue, circulating, spatial, and imaging biomarkers. Controlled clinical studies are required to determine whether macrophage-directed interventions can improve existing lung cancer treatments.

Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous and fatal neurodegenerative disorder, for which clinical management and drug development have long faced formidable challenges. Since the approval of riluzole and edaravone, dozens of promising drug candidates that showed efficacy in preclinical models have failed in Phase III trials, highlighting an urgent need for systematic re-evaluation of the field. This review provides a comprehensive summary of the major limitations of current clinical therapies for ALS. These include the modest survival benefit of riluzole, the narrow eligible population for edaravone, and the complex trajectory of sodium phenylbutyrate-taurursodiol, which received accelerated approval but was subsequently voluntarily withdrawn after its confirmatory Phase III trial failed to meet its primary endpoints. On this basis, we discuss four major challenges that contribute to clinical trial failures: disease heterogeneity, paucity of reliable biomarkers, insufficient translational validity of preclinical models, and inherent flaws in conventional trial designs. Subsequently, we discuss emerging therapeutic strategies, encompassing precision medicine and gene therapy (exemplified by the development of the antisense oligonucleotide tofersen for SOD1-ALS), targeting protein homeostasis, modulation of neuroinflammation, metabolic and energetic support, neuroprotection and regeneration, as well as multi-target combination approaches. Innovative trial designs, including adaptive platform trials (exemplified by the HEALEY ALS Platform Trial), enrichment designs, sequential designs, N-of-1 trials, and virtual clinical trials are fundamentally reshaping the drug development paradigm in ALS. In conclusion, ALS treatment is at a historic turning point from a "one-size-fits-all” approach toward "precisely stratified” medicine. Future success depends on establishing multimodal biomarker panels, implementing genetic testing-guided individualized therapy, developing combination regimens, and integrating patient-reported outcomes with palliative care. Although substantial challenges remain, the clinical success of Tofersen provides evidence that precision therapeutic strategies may gradually transform ALS management toward a more individualized and disease-modifying approach.

Skeletal muscle regeneration is essential for recovery after injury and for maintaining physical and metabolic function. This capacity declines with aging and is often impaired in chronic diseases, limiting effective repair. This review summarizes the main mechanisms that regulate muscle repair, with a focus on satellite cell activity and its interaction with inflammatory, metabolic, vascular, and fibrotic signals at the molecular and cellular level. We discuss how these processes are disrupted in aging, Duchenne muscular dystrophy, chronic obstructive pulmonary disease, diabetes, chronic kidney disease, and cancer cachexia, leading to delayed repair, reduced myogenic differentiation, and fibrosis. We also review current and emerging strategies to improve muscle regeneration, including exercise, bioactive molecules, physical stimulation, gene-based approaches, engineered biomaterials, and cell or cell-derived therapies. Across these conditions, chronic inflammation, metabolic dysfunction, and fibrotic remodeling appear to be common barriers to effective regeneration. Multi-target therapeutic approaches may offer advantages over single-pathway interventions, although clinical evidence is still limited; initial preclinical results, however, are promising.

The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, the core DNA-sensing mechanism in innate immunity, plays a pivotal role in linking tumorigenesis and the immune response. This review systematically elucidates the molecular activation mechanisms of this pathway and its complex regulatory networks within tumors, with a particular focus on analyzing its dual functions—tumor immune surveillance versus tumor promotion—and the determining factors involved. Current research indicates that acute activation of the cGAS–STING pathway potently suppresses tumors by inducing type I interferon responses, thereby promoting dendritic cell (DC) maturation and cytotoxic T lymphocyte infiltration. However, its chronic, persistent activation can paradoxically accelerate tumor progression and immune evasion by remodeling the immunosuppressive tumor microenvironment (TME), inducing chronic inflammation, and enhancing the intrinsic malignant phenotypes of tumor cells. Tumor cells tightly regulate the activity of this pathway through multiple mechanisms, including epigenetic silencing, aberrant post-translational modifications, autophagy-dependent degradation, and tumor microenvironment remodeling. Based on these findings, this review comprehensively summarizes therapeutic strategies targeting the cGAS–STING pathway. These include the latest advancements in STING agonist development, optimization strategies for combination therapies, and innovative applications of nano-delivery systems. Furthermore, we delve into the critical challenges hindering current clinical translation, including pharmacokinetic limitations, mechanisms of tumor resistance, STING genetic polymorphisms, and safety concerns. Finally, we explore future research directions, encompassing precision modulation strategies, personalized therapeutic approaches, and novel delivery systems, aiming to provide a theoretical foundation and innovative insights for the next generation of cancer immunotherapies centered on the cGAS–STING pathway.

Lung cancer is the leading cause of global cancer mortality, with treatment efficacy limited by high heterogeneity, drug resistance, and an immunosuppressive tumor microenvironment. Focusing primarily on non-small cell lung cancer (NSCLC), this review systematically analyzes eight key regulated cell death (RCD) pathways in lung cancer. These pathways are apoptosis, autophagy, necroptosis, ferroptosis, cuproptosis, pyroptosis, immunogenic cell death (ICD), and lysosome-dependent cell death (LDCD). Mechanistic dissection reveals complex crosstalk and a dynamic equilibrium among these pathways. For instance, apoptosis escape via EGFR/PI3K/Akt/mTOR signaling promotes survival, while autophagy exhibits a context-dependent dual role regulated by factors such as RBBP4 and the AURKA-CXCL5 axis. Importantly, several RCD pathways exert potent immunomodulatory functions. Necroptosis activates T cells by releasing damage-associated molecular patterns (DAMPs), while ferroptosis enhances NK cell cytotoxicity through GPX4 inactivation. Regarding therapeutic advances, synergistic strategies show promise, such as berberine with EGFR-TKIs inducing apoptosis via EGFR degradation, and (-)-Guaiol triggering ICD to synergize with PD-1/PD-L1 inhibitors. Novel inducers, including Auranofin (ferroptosis), TMEM100 agonists (necroptosis), and cuproptosis nanomedicines (e.g., DE-Cu ₄ O ₃ NPs), demonstrate preclinical potential. Prognostic models based on RCD-related genes (e.g., LDCD signatures) can predict immune features and response to immune checkpoint inhibitors (ICIs). However, clinical translation faces bottlenecks, including intricate pathway crosstalk, difficulties in remodeling the immunosuppressive niche, low ICI response in EGFR-mutant patients, and a lack of standardized biomarkers and optimized delivery systems. Future research should prioritize coordinated targeting of multiple death pathways, utilize advanced computational tools integrated with multi-omics data to decipher RCD network complexity and optimize treatment prediction, and strengthen interdisciplinary translational efforts. Ultimately, a deep understanding of the RCD network paves the way for a paradigm shift toward precision therapy in lung cancer.