Cerebral ischemia-reperfusion injury (CIRI) is a complex pathological process triggered by transient obstruction of blood flow and subsequent reperfusion, ultimately leading to intracellular disturbances such as oxidative stress, inflammatory responses, and programmed cell death. Among the various types of cell death, pyroptosis (an inflammatory kind of regulated cell death) has received increasing attention due to its involvement in key neurovascular unit cells, including endothelial cells, neurons, microglia, and astrocytes. Intriguingly, accumulating evidence demonstrates that non-coding RNAs (ncRNAs), including long non-coding RNAs, microRNAs, and circular RNAs, can modulate multiple stages of pyroptosis in CIRI. This review synthesizes recent findings on the ncRNAs-regulated pyroptosis in CIRI. We highlight the molecular underpinnings of pyroptotic activation following ischemic injury and discuss how ncRNAs shape these mechanisms. By elucidating the interactions between ncRNAs and pyroptosis-related pathways, we intend to present innovative viewpoints for early diagnosis and the development of potential therapeutic strategies to mitigate CIRI.

With the accelerated pace of global population aging, the number of people suffering from age-related diseases is increasing, posing a serious threat to human health and well-being. Age-related diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), hypertension, atherosclerosis, type 2 diabetes (T2DM), and osteoporosis (OP), are often characterized by physiological function decline and metabolic disorders caused by aging, among which dysregulation of metal ion homeostasis, especially copper homeostasis imbalance, has emerged as a major factor. Copper is an essential enzymatic cofactor whose homeostasis is tightly regulated at systemic, cellular, and subcellular levels. However, during the aging process, the balance between copper uptake and efflux becomes compromised, alongside a reduction in cellular copper-buffering capacity. These alterations may lead to the loss of copper homeostasis and induce cuproptosis, which is a recently elucidated form of regulated cell death (RCD) triggered by copper overload and disrupts mitochondrial metabolism by promoting the aggregation of lipoylated proteins in the tricarboxylic acid cycle (TCA) and destabilizing respiratory chain complexes. Copper homeostasis imbalance and the resulting cuproptosis accelerate the aging process by promoting molecular mechanisms, including telomere attrition, mitochondrial dysfunction, oxidative stress, proteostasis imbalance, epigenetic changes, and chronic inflammation. This review focuses on the reciprocal interactions between aging and copper homeostasis: it elucidates how aging impairs copper homeostatic regulation, and how dysregulated copper metabolism and subsequent cuproptosis accelerate aging and exacerbate age-related diseases. Furthermore, it explores potential therapeutic strategies targeting copper homeostasis and cuproptosis to treat age-related diseases.

Ischemic stroke is a debilitating condition characterized by high morbidity, disability, recurrence, and mortality rates on a global scale, posing a significant threat to public health and economic stability. Extensive research has thoroughly explored the molecular mechanisms underlying ischemic stroke, elucidating a strong association between soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor proteins (SNAREs) and the pathogenesis of this condition. SNAREs, a class of highly conserved proteins involved in membrane fusion, play a crucial role in modulating neuronal information transmission and promoting myelin formation in the central nervous system (CNS). Preventing the SNARE complex formation, malfunctions in SNARE-dependent exocytosis, and altered regulation of SNARE-mediated vesicle fusion are linked to excitotoxicity, endoplasmic reticulum (ER) stress, and programmed cell death (PCD) in ischemic stroke. However, its underlying mechanisms remain unclear. This study conducts a comprehensive review of the existing literature on SNARE proteins, encompassing the structure, classification, and expression of the SNARE protein family, as well as the assembly - disassembly cycle of SNARE complexes and their physiological roles in the CNS. We thoroughly examine the mechanisms by which SNAREs contribute to the pathological progression and associated risk factors of ischemic stroke (hypertension, hyperglycemia, dyslipidemia, and atherosclerosis). Furthermore, our findings highlight the promise of SNAREs as a viable target for pharmacological interventions in the treatment of ischemic stroke.

Ischemia–reperfusion injury (IRI) is a prevalent pathological process in clinical settings characterized by complex pathogenesis involving the interplay of oxidative stress, inflammation, mitochondrial dysfunction, and diverse cell death pathways. Fundamentally, IRI manifests as a complication arising from reperfusion therapies aimed at restoring blood flow following ischemia. Despite the existence of various therapeutic strategies, the development of effective interventions for IRI remains a significant challenge. Rutin, a low-molecular-weight flavonoid glycoside ubiquitously present in vegetables, fruits, and herbal medicines, exhibits promising therapeutic potential due to its pleiotropic biological activities, including antioxidant, anti-inflammatory, and cytoprotective effects against cell death. This review systematically elucidates the molecular mechanisms underlying the protective effects of rutin against IRI and synthesizes evidence from preclinical studies regarding its diverse modes of action. However, the clinical application of rutin is currently hampered by its relatively low bioavailability. Future research should prioritize the development of innovative pharmaceutical formulations to enhance its bioavailability, thereby fully unlocking its clinical translational value.