Multifaceted roles of S100A6 in neurological disorders: expression, interaction networks, and clinical implications

The Multifaceted Role of the P2X7 Receptor in Alzheimer's Disease: A Unifying Pathological Link.

S100A8/A9 in Kidney Diseases: Mechanisms, Spatiotemporal Regulation, Biomarker Potential, and Therapeutic Implications

: S100A8/A9 (calprotectin) is increasingly recognized as an inflammatory mediator and a potential biomarker and therapeutic target in kidney diseases. However, its roles appear to vary across different stages and contexts of renal injury and repair, yet these changes remain incompletely understood. This narrative review synthesizes evidence from PubMed, Web of Science, and Scopus, supplemented by manual reference screening. Current evidence indicates that S100A8/A9 promotes immune activation, tubular injury, and fibrotic remodeling in diverse renal disorders. Emerging findings further suggest that its effects vary according to disease stage, cellular source, receptor usage, and the local microenvironment, with S100A8/A9 predominantly amplifying early inflammatory injury while potentially contributing to inflammation resolution and tissue repair at later stages. We therefore propose a spatiotemporal framework that extends beyond previous disease-or pathway-centered perspectives by integrating the timing and cellular context of S100A8/A9 signaling. Altered S100A8/A9 levels in blood, urine, feces, and extracellular vesicles also show potential for disease detection, differential diagnosis, monitoring, and prognostic assessment, while pharmacological inhibition of this axis has produced renoprotective effects in preclinical models. Nevertheless, heterogeneous models, limited cell-and receptor-specific evidence, uncertain therapeutic windows, and insufficient prospective clinical validation hinder translation. Longitudinal clinical studies and spatial and single-cell analyses are needed to establish stage-specific biomarker and therapeutic strategies targeting S100A8/A9 in precision nephrology.

MEOX2: a homeobox transcription factor with multifaceted biological functions and broad disease associations

The mesenchymal homeobox transcription factor MEOX2 is recognized for its roles in development and homeostasis, but the full landscape of its complex and often contradictory functions in human diseases, along with its potential unifying regulatory logic, remains to be systematically elucidated. This Review synthesizes current evidence to provide a comprehensive overview of MEOX2’s widespread roles in both neoplastic and non-neoplastic diseases. MEOX2 is remarkably context-dependent: it acts as an oncogene in glioblastoma and lung cancer, but as a tumour suppressor in breast cancer, hepatocellular carcinoma and other tumour types. Its dysregulation is also linked to neurovascular deficits in Alzheimer disease (AD), cardiovascular disorders, metabolic fibrosis and developmental malformations. This functional versatility stems from MEOX2’s role as a key signalling integrator, subject to fine-tuned regulation by epigenetic mechanisms, non-coding RNA networks and core pathways including PI3K/AKT, ERK and Hedgehog (Hh). Given the strong association between MEOX2 expression and clinical outcomes, it has emerged as a potential diagnostic and prognostic biomarker for several diseases. Intervention strategies targeting MEOX2 and its regulatory networks show translational promise. This Review proposes a conceptual framework placing MEOX2 as a ‘cross-disease core regulatory node’, systematically delineates its complex disease associations and molecular mechanisms, and charts a course for the future development of precision medicine strategies targeting MEOX2.

Emerging roles of granzymes in neurodegeneration and neuroinflammation: mechanistic insights and therapeutic opportunities

Neurodegenerative diseases are increasingly recognized as disorders shaped not only by intrinsic neuronal vulnerability, but also by chronic neuroinflammation mediated by maladaptive neuroimmune signaling. Granzymes, a family of serine proteases classically studied for their cytotoxic roles in anti-viral and anti-tumor immunity, are emerging as important mediators of central nervous system (CNS) pathology. In addition to their canonical intracellular functions, granzymes can act extracellularly to cleave the extracellular matrix (ECM), activate cell-surface receptors, disrupt epithelial barrier function, amplify inflammatory cascades, and alter glial and neuronal responses to injury. In this review, we synthesize current knowledge on the roles of Granzyme A (GzmA), Granzyme B (GzmB), Granzyme H (GzmH), and Granzyme K (GzmK) in neurodegeneration and neuroinflammation across diverse CNS disease and injury contexts, such as Alzheimer’s disease (AD), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and age-related macular degeneration (AMD). GzmB is the most extensively characterized, with evidence supporting both intracellular neurotoxicity and extracellular pathogenic functions mediated through protease-activated receptor signaling, ECM cleavage, outer blood–retina barrier disruption, angiogenesis, fibrosis, and chronic inflammation. GzmA is implicated in tau proteolysis and structural destabilization of neurons and astrocytes, while GzmK has emerged as a context-dependent regulator of neuroinflammation through PAR-1 activation, microglial modulation, and complement cascade activation. GzmH remains the least understood but may contribute to nerve injury through mechanisms that are only beginning to be defined. We also discuss endogenous and pharmacological granzyme inhibition, highlighting the therapeutic promise of selective extracellular granzyme targeting, particularly for GzmB, while emphasizing the current lack of selective inhibitors for GzmA, GzmK, and GzmH. Collectively, these findings position granzymes as underappreciated neuroimmune effectors and potential therapeutic targets in neurodegenerative diseases and CNS injury.

PP2A: Decoding Its Structure, Regulation and Therapeutic Applications in Neurological Disorders.

Protein phosphatase 2A (PP2A) is a highly conserved serine/threonine phosphatase that plays a pivotal role in maintaining cellular homeostasis by counterbalancing kinase activity. As a heterotrimeric enzyme composed of scaffolding, regulatory, and catalytic subunits, PP2A achieves extraordinary functional diversity through the dynamic assembly of more than 80 holoenzyme variants. This structural versatility allows PP2A to regulate a wide range of biological processes, including cell cycle progression, apoptosis, DNA damage response, and major signaling pathways such as MAPK and Wnt. Dysregulation of PP2A, through altered subunit expression, post-translational modification, or inhibition by endogenous suppressors like CIP2A and SET, has been implicated in diverse diseases, notably neurodegenerative disorders, cancers, and metabolic syndromes. In neurological disorders such as Alzheimer's and Parkinson's diseases, impaired PP2A activity contributes to pathogenic protein hyperphosphorylation, neurofibrillary tangle formation, and neuroinflammation. Recent advances have fundamentally reshaped our understanding of PP2A biology. High-resolution structural studies have revealed the molecular basis of holoenzyme assembly and substrate recruitment, while accumulating evidence suggests that PP2A activity is dynamically regulated across tissues and cell types, largely driven by differential expression of regulatory subunits and post-translational modifications. Despite these advances, current knowledge remains fragmented, and a comprehensive synthesis linking PP2A structural dynamics, regulatory mechanisms, and its roles in pathophysiology, particularly in the context of neurological disorders, is still lacking. This review deciphers the structural complexity and regulatory mechanisms of PP2A, elucidates its multifaceted roles in neural physiology and pathology, and examines current and emerging therapeutic strategies targeting PP2A modulation to intervene in neurological disease.

Epitranscriptomic imprints on glial cell polarization: METTL3/IGF2BP2 axis as a driver of neurodegeneration in Alzheimer's disease.