IDH-wildtype, high-grade glioma with predominantly astrocytic differentiation and classified as glioblastoma in the current WHO classification of central nervous system tumors is among the most common and aggressive primary malignant brain tumors. Glioblastoma remains largely refractory to current therapies, leading to early recurrence and poor prognosis. In nearly all glioblastomas, the p53 tumor-suppressor pathway is functionally inactivated, either through TP53 mutations or through deregulated signaling pathways that promote p53 degradation. This review provides a comprehensive and up-to-date overview of gene therapy strategies designed to restore p53 function or exploit p53 loss-of-function in glioblastoma. In particular, it critically discusses the biological barriers and technical limitations of viral and non-viral nucleic acid delivery systems that have contributed to inadequate clinical outcomes, while also highlighting recent advances with potential to reinvigorate p53 function in glioblastoma.

Global population aging has increased the incidence of intractable diseases. Accordingly, regenerative medicine using stem cell therapies offers a critical shift from symptom management to functional tissue restoration. Hematopoietic, mesenchymal, and pluripotent stem cells (embryonic and induced pluripotent stem cells) have shown promising therapeutic potential. However, their clinical translation is constrained by persistent biological, manufacturing, and regulatory hurdles associated with genomic instability, tumorigenic risk, and batch-to-batch heterogeneity. This review provides a comprehensive overview of the current stem cell research landscape, highlighting the strategic shift from traditional cell-centric development to a multi-disciplinary and technology-driven approach. Emerging technologies, including three-dimensional organoids, advanced biomaterials, genome editing, and artificial intelligence-integrated automated manufacturing, are actively resolving long-standing translational bottlenecks to ensure scalable, safe, and reproducible clinical implementation. Regulatory approaches differ across major countries; however, the trend toward incorporating patient needs is growing. This has accelerated access to innovative therapies, with ongoing efforts to ensure that these advances do not compromise safety or efficacy. Moving forward, the successful clinical integration of next-generation stem cell therapeutics is likely to be shaped by the synergy between harmonized regulatory requirements and reliable real-world evidence. Collectively, these factors serve to bridge the transition from early patient access to definitive licensing.

Adiponectin is an adipocyte-derived hormone with broad cardiometabolic benefits, circulating at high levels in healthy individuals but reduced in obesity, diabetes, and cardiovascular disease. Low adiponectin concentrations are strongly associated with coronary artery disease, myocardial infarction, myocardial ischemia-reperfusion injury (MIRI), and heart failure. MIRI remains a major unmet need in contemporary ST-segment-elevation myocardial infarction (STEMI) care. Although reperfusion is essential in limiting ischemic myocardial necrosis, it causes deleterious effects such as impaired carbohydrate oxidation, excessive fatty-acid oxidation, intracellular acidosis, calcium (Ca[2+]) overload, oxidative/nitrative stress, and mitochondrial fragmentation, that expand infarct size, worsen microvascular obstruction, and fuel adverse ventricular remodeling. Activation of the adiponectin-adiponectin receptor (AdipoR) axis directly counteracts these processes by stimulating adenosine monophosphate-activated protein kinase (AMPK)-dependent metabolic rebalancing, restoring mitochondrial fusion-fission homeostasis, enhancing oxidative capacity, reducing inducible nitric oxide synthase (iNOS-) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated injury, improving endothelial nitric oxide (NO) bioavailability, and enhancing microvascular perfusion. In animal models, adiponectin or its mimetics consistently reduced infarct size, improved myocardial function, and attenuated apoptosis, inflammation, and no-reflow. A growing array of therapeutic strategies has emerged, each bringing its own pharmacologic nuances and implications for translation to the clinic. This review summarizes current strategies to enhance adiponectin action, highlights the progress in peptide and small-molecule mimetics, and discusses future directions for clinical translation in cardiometabolic diseases.

Alzheimer's disease (AD) remains a major cause of dementia, yet effective disease-modifying therapies are still limited. Although amyloid-β (Aβ) and tau pathology remain core features of AD pathogenesis, they do not fully explain how these pathological alterations drive progressive cellular dysfunction. Increasing evidence suggests that mitochondria are involved at this critical interface. In AD, mitochondrial abnormalities impair energy production, compromise organelle quality control, disrupt calcium (Ca[2+]) homeostasis, and alter communication with the endoplasmic reticulum and glial cells. As these defects accumulate, neurons and glia become less able to maintain metabolic stability, redox balance, and synaptic function. Mitochondrial dysfunction is therefore relevant to AD not as a single isolated lesion, but as a convergent process through which metabolic failure, oxidative stress, mitochondrial DNA damage, inflammatory signaling, and defective cellular maintenance reinforce one another. This perspective also helps explain why disease progression is difficult to reverse once mitochondrial homeostasis has been broadly compromised. At the same time, this framework also points to therapeutic opportunities, as the mechanisms driving the development and progression of mitochondrial dysfunction may be amenable to intervention. However, many mitochondria-centered strategies remain preclinical or have yielded inconsistent clinical benefit. Current evidence supports mitochondrial dysfunction as both a useful mechanistic basis for understanding AD progression and a biologically meaningful, though challenging, therapeutic target.

Sinoatrial node dysfunction (SND) is a major cause of bradyarrhythmia, chronotropic incompetence, tachy-brady syndrome, and a common indication for permanent pacemaker implantation, particularly in older adults. Although SND has diverse etiologies, this review focuses on aging-associated intrinsic SND, while considering other common causes where they inform differential diagnosis, arrhythmogenic mechanisms, or therapeutic development. Although current medical interventions provide effective rhythm support, they do not correct the molecular and tissue-level processes that drive sinoatrial node (SAN) degeneration. The review integrates current knowledge of SAN biology with mechanisms underlying SND, including fibrosis, ion-channel and calcium-clock remodeling, mitochondrial dysfunction, cellular senescence, impaired β-adrenergic signaling, genetic susceptibility, and epigenetic or epitranscriptomic regulation. We further discuss how these mechanisms contribute to impaired impulse generation, SAN exit block, reduced chronotropic reserve, and increased susceptibility to atrial arrhythmia. We discuss approaches for studying the molecular and cellular mechanisms and evaluating therapeutic strategies using emerging animal models, human pluripotent stem cell-derived SAN-like pacemaker cells, organoids, assembloids, and single-cell and spatial omics platforms. Finally, we highlight translational opportunities, including senescence-directed, metabolic, antifibrotic, autonomic, gene-based, regenerative, and biological pacing strategies. A mechanism-guided classification of SND may support future precision therapies that complement conventional pacing by linking dominant rhythm phenotypes to targetable biological drivers, molecular and functional pharmacodynamic markers, and human-relevant models of pacemaker failure.

Spinal motor dysfunction after injury or prolonged disuse remains a major clinical challenge, in part because disruption of chloride homeostasis can weaken inhibitory control in spinal motoneurons. The cation-chloride cotransporters KCC2 and NKCC1 are central molecular regulators of intracellular chloride concentration ([Cl[-]]ᵢ), and their relative activities strongly influence efficacy of GABAergic and glycinergic inhibition. Following injury or reduced activity, changes in neuronal signaling, inflammation, and mechanical unloading can impair KCC2 function and alter NKCC1 activity, thereby shifting Cl[-] gradients and reducing the effectiveness of inhibitory neurotransmission. These changes have been implicated in motoneuron hyperexcitability, spasticity, and abnormal reflex function. Here, we review the molecular mechanisms that regulate KCC2 and NKCC1 in spinal motoneurons under physiological and pathological conditions. Particular attention is given to activity-dependent pathways, including BDNF-TrkB, WNK-OSR1/SPAK, and HDAC-dependent regulation, and to their effects on transporter abundance, phosphorylation, and function. We also examine the therapeutic prospects of restoring Cl[-] homeostasis, with emphasis on KCC2-enchancing compounds such as CLP290, NKCC1 inhibitors such as bumetanide, and approaches that combine pharmacological intervention with activity-based rehabilitation. Rather than considering these strategies in isolation, we discuss how their efficacy may depend on the underlying pathology, disease stage, and state of neuronal activity. We conclude by identifying important gaps in our understanding of Cl[-] regulation in spinal motor disorders and by considering the experimental and translational steps needed to determine whether modulation of KCC2 and NKCC1 can provide meaningful therapeutic benefit.

Transposable elements (TEs), commonly known as "jumping genes," constitute nearly half of the human genome and are increasingly recognized as important regulators of gene expression, chromatin organization, and immune signaling. Although most TEs are epigenetically silenced under physiological conditions, aging, chronic inflammation, and cancer can induce TE reactivation, leading to genomic instability, innate immune activation, and transcriptional reprogramming. Emerging evidence demonstrates that TEs contribute to immune cell differentiation, enhancer landscape formation, interferon signaling, and inflammatory responses through diverse mechanisms, including the generation of regulatory non-coding RNAs, alternative splicing events, and TE-derived peptides presented by major histocompatibility complex molecules. In addition to their roles in cancer biology, dysregulated TE activities have also been implicated in aging-associated and inflammatory disorders. In this review, we summarize the classification and regulatory functions of TEs, discuss their roles in immune regulation, inflammation and cancer, and examine emerging therapeutic strategies targeting TE-associated pathways in cancer and inflammatory diseases.

Disruption of circadian blood pressure (BP) rhythm is a key pathophysiological feature and an important marker of cardiovascular risk. Ambulatory BP monitoring, the gold standard for assessing BP circadian patterns, has revealed that non-dipper and reverse-dipper phenotypes are strong independent predictors of coronary artery disease, atrial fibrillation, heart failure, and all-cause mortality. Notably, even when daytime BP is adequately controlled, abnormal circadian BP profiles impose sustained cardiovascular stress, accelerating target organ damage, including left ventricular hypertrophy, atherosclerosis, atrial remodeling, and renal impairment. Accordingly, assessment of BP circadian rhythm has become an essential component of contemporary hypertension management. It not only helps to accurately identify high-risk patients who might be missed by conventional office BP measurements but also provides a knowledge basis for optimizing antihypertensive medication strategies according to individual rhythm classification to restore physiological nighttime BP pattern. We summarize evidence from clinical trials evaluating chronotherapy for BP control and discuss current guideline recommendations worldwide. Despite growing interest, important knowledge gaps remain, including incomplete understanding of underlying mechanisms and substantial interindividual variability in treatment response, underscoring the need for precision, rhythm-guided therapeutic approaches supported by robust outcome-based evidence.

Multidrug resistance (MDR) remains a major challenge in cancer treatment. MDR has been explained by single-gene mechanisms, such as overexpression of ATP-binding cassette (ABC) transporters, drug-target mutations, activation of bypass signaling pathways, and increased DNA repair. However, these mechanisms alone are insufficient to explain the heterogeneity, reversibility, temporal evolution, and environmental dependence of drug resistance observed in clinical settings. Increasing evidence suggests that MDR is better viewed as a complex and evolving biological phenomenon rather than the result of isolated molecular events. This shift in perspective presents both challenges and opportunities for drug development. Future strategies will therefore require dynamic and mechanism-informed approaches that integrate rational drug combinations with sequential, intermittent, or adaptive treatment according to the evolving resistance state. In this review, we propose a conceptual shift from conventional MDR models toward systemic adaptive resistance. We review classical drug resistance, including drug uptake/efflux, compensatory pathway activation, and apoptosis evasion. We explore non-genetic drug resistance, such as drug-tolerant persisters (DTPs), epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) plasticity, and related factors. Then, we discuss the interaction between these mechanisms, and how their coordinated effects contribute to tumor persistence and the evolution of MDR. Finally, we evaluate barriers in translational medicine and emerging pharmacological strategies, including longitudinal molecular monitoring and artificial intelligence (AI) -assisted drug resistance prediction.

Immune checkpoint inhibitor (ICI) resistance remains a major challenge. This review discusses emerging evidence that neuroregulation constitutes an underrecognized regulatory layer in ICI resistance and summarizes its mechanistic, biomarker, and therapeutic implications. Mechanistically, neural components can modulate antitumor immunity through signaling, structural, spatial, and metabolic routes. Neural signaling may contribute to T-cell dysfunction by stabilizing exhausted phenotypes, increasing the expression of inhibitory receptors, and suppressing effector cytokine production. Neuroglial cells and neuropeptides further exacerbate immunosuppression through the induction of regulatory T cells and the reprogramming of myeloid cells. Beyond causing functional impairment, neuroregulation alters the spatial distribution of immune cells by inhibiting chemokine networks essential for the recruitment of dendritic cells and cytotoxic T cells, thereby promoting immune-excluded and immune-cold tumor states. Neural injury creates perineural immunosuppressive niches enriched in immunoregulatory tumor-associated macrophage states and regulatory T cells, which can extend into the broader tumor microenvironment and restrict CD8[+] T-cell infiltration and function. Neural inputs also reshape the metabolism of tumor and immune cells, establishing neuro-metabolic-immune circuits that limit effector cell fitness and reinforce ICI resistance. Therapeutically, pharmacological targeting of neural pathways, along with emerging bioelectronic and ex vivo neuro-immune strategies, may enhance the efficacy of ICIs across various tumor models. Neural abundance and injury signatures also emerge as potentially clinically relevant biomarkers that complement immune-centric predictors of response. Overall, neuroregulation provides a biologically coherent and potentially targetable framework for understanding and overcoming ICI resistance.

Galectin-3, a β-galactoside-binding lectin, is a driver and regulator of inflammation and fibrosis, and its levels are elevated in some heart and lung diseases. It also serves as a biomarker for the risk and severity of some forms of heart failure and, potentially, for various other pathological conditions. These observations make galectin-3 a promising potential therapeutic target. Both genetic and pharmacological inhibition of galectin-3 have been shown to ameliorate renal dysfunction and exert protective effects against liver fibrosis in animal models. Several galectin-3 inhibitors have been developed for therapeutic application in various pathological conditions. This review examines the progress of the development of 161 galectin-3 inhibitors, including monosaccharides, oligosaccharides, natural polysaccharides and their derivatives, carbohydrate polymers, antibody-drug conjugates, and non-carbohydrate compounds. Structure-activity relationships are emerging for these inhibitors, and the atypical binding pockets of galectin-3 have informed the development of a pharmacophore model that is expected to guide the design and discovery of potent, selective inhibitors for treatment of cancer, inflammation, and fibrosis.

B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common form of paediatric cancer and is characterised by the clonal expansion of immature B lymphocytes. The advent of targeted therapies has transformed BCP-ALL from a largely fatal disease to one which is well managed under current protocols. Continued refinements to disease classification have facilitated the identification of novel drug targets that underscore much of this change. Despite this progress, some patients remain unclassified by current conventions, and have not profited from the era of targeted therapy. Relapsed disease likewise remains a major challenge, and although new immunotherapies have gone a long way, additional strategies are needed. Addressing these issues requires a concerted effort to identify novel drug targets. Here, we discuss the origins and classification of BCP-ALL, before outlining the therapeutic advances that have considerably improved disease outlook over the last few decades. We then outline the latest trends in disease treatment, and propose how recent discoveries may translate into new therapeutic approaches.

Depression remains a leading cause of disability worldwide with a rapidly escalating disease burden, yet current pharmacotherapies are limited by delayed onset of action, insufficient efficacy in treatment-resistant depression, and troublesome adverse effects. This review provides a systematic and critical evaluation of pharmacological mechanisms in depression and related therapeutic targets. We examine established targets spanning the neurotransmitters corresponding to serotonergic, glutamatergic, GABAergic, and dopaminergic systems, alongside emerging glial gap junctions and inflammatory perspectives. For each target, we assess the quality of evidence from preclinical studies and clinical trials, discuss corresponding antidepressant drug classes, and identify knowledge gaps. Finally, we propose future directions for antidepressant drug development, including novel target discovery, rational multi-target design, and optimization of preclinical-to-clinical translation. By providing a pharmacology-driven roadmap of druggable targets and their therapeutic mechanisms, this review aims to inform both mechanistic understanding and drug discovery efforts in depression.

Traumatic spinal cord injury (SCI) is a devastating condition that affects millions of people worldwide and remains without effective pharmacological therapies that substantially improve neurological recovery. A major barrier to repair is the persistent secondary neuroinflammatory response that evolves over weeks to months after injury. Although neuroinflammation represents an attractive therapeutic target, broadly acting immunosuppressive approaches have yielded limited clinical benefit, highlighting the need to identify mechanisms that drive detrimental inflammation while preserving beneficial immune functions that support repair. Emerging evidence identifies dysregulated lipid handling as one such mechanism. SCI generates a substantial lipid burden through myelin and cellular breakdown, while lipidomic and metabolomic studies reveal persistent, dynamic alterations in lipid processing, storage, and transport. The capacity of resident glia and infiltrating immune cells to manage this lipid burden has important consequences for inflammatory state and tissue repair. Apolipoprotein E (ApoE), a major regulator of lipid transport and redistribution in the central nervous system, lies at the intersection of these processes, linking lipid metabolism with neuroinflammation and recovery after SCI. Here, we critically evaluate ApoE biology and its relationship to lipid dysregulation after SCI, together with preclinical evidence targeting ApoE-associated and broader lipid-regulatory pathways, including ApoE mimetics, LXR/RXR and PPARγ signaling, and statins. We distinguish demonstrated therapeutic mechanisms from proposed ApoE-dependent effects and evaluate emerging clinical evidence for lipid-modifying interventions in SCI. Finally, we consider key barriers to translation, including injury heterogeneity, sex, age, ApoE genotype, timing and delivery method, and how lipid-directed interventions can be integrated into multimodal strategies for SCI repair. Together, current evidence identifies dysregulated lipid handling as a mechanistically important and potentially tractable component of secondary SCI pathology, while highlighting the critical studies needed to determine whether ApoE-directed and broader lipid-modifying strategies can improve neurological recovery.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by hepatic steatosis, inflammation, and fibrosis, which can ultimately lead to cirrhosis and hepatocellular carcinoma. Although recent Food and Drug Administration approvals of resmetirom and semaglutide mark a milestone in MASH therapy, no approved agents directly target hepatic inflammation or fibrosis, underscoring the urgent need for novel therapeutic strategies. Hepatocyte death is a histological hallmark that distinguishes MASH from simple steatosis, yet the mechanisms by which it drives chronic inflammation and fibrosis remain incompletely understood. We identified hepatic crown-like structures (CLSs), aggregates of macrophages surrounding dead hepatocytes, as the histological hub of this process. In steatotic livers, impaired dead cell clearance allows sustained macrophage-dead cell interactions within CLSs, where tissue-resident macrophages acquire profibrotic properties. Cholesterol accumulation in hepatocytes promotes cholesterol crystallization, triggering hepatocyte death and subsequent lysosomal cholesterol overload in CLS-constituting macrophages, thereby accelerating inflammation and fibrosis. Targeting this pathway using a liver-tropic supramolecular β-cyclodextrin polyrotaxane (βCD-PRX), which selectively delivers βCD to lysosomes via endocytosis, ameliorated macrophage lysosomal stress and hepatic fibrosis in murine MASH models without affecting body weight or steatosis. Beyond the liver, CLS-driven chronic inflammation contributes to adipose tissue dysfunction in obesity and the transition from acute kidney injury to chronic kidney disease, suggesting broad therapeutic relevance. Continued investigation of CLSs as a shared pathological microenvironment across metabolic diseases may pave the way for novel diagnostic and therapeutic modalities for MASH and related conditions.