Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and frontotemporal dementia, collectively represent one of the most pressing global health challenges. Despite major advances in our understanding of neuronal vulnerability, synaptic failure, and cell death pathways, effective disease-modifying therapies remain limited. A fundamental barrier to progress is the insufficient integration of emerging molecular biomarkers — including metabolomic, lipidomic, and redox signatures — with mechanistic insights that reveal new therapeutic targets. Early, accurate diagnosis and timely intervention require biomarkers that reflect pathological processes at their earliest stages, while successful therapeutic development depends on identifying key molecular drivers that are accessible to pharmacological, genetic, or immunological modulation.

In recent years, rapid advances in multi-omics profiling (particularly metabolomics and lipidomics), single-cell sequencing, spatial transcriptomics, high-resolution neuroimaging, biofluid biomarker discovery, and human stem-cell-derived disease models have produced unprecedented opportunities to redefine both diagnostic and therapeutic landscapes. Metabolomics has emerged as a powerful tool for capturing dynamic alterations in energy metabolism, oxidative stress, mitochondrial bioenergetics, neurotransmitter homeostasis, and lipid remodeling — all of which are central to neurodegeneration. Novel biomarkers now span fluid indicators of proteostasis breakdown, mitochondrial dysfunction (e.g., TCA cycle intermediates, acyl-carnitines, redox couples), neuroenergetic failure, lipid dyshomeostasis, glial metabolic reprogramming, neuroimmune metabolic shifts, and synaptic integrity. These metabolic signatures are increasingly used for patient stratification, prodromal detection, disease monitoring, and precision-medicine-based treatment strategies.

Parallel progress in target discovery has highlighted diverse pathogenic mechanisms such as impaired protein clearance, neuroinflammation, mitochondrial and lysosomal dysfunction, aberrant cellular energetics, dysregulated lipid signaling, and RNA-binding protein pathology. Metabolomic studies have particularly illuminated targetable nodes in central carbon metabolism, one-carbon metabolism, polyamine synthesis, and phospholipid remodeling that link genetic risk factors to functional decline. Together, these discoveries point toward a new era in which genomic, proteomic, and metabolomic biomarkers can be co-developed with therapeutic targets for disease interception and modification.

This Special Issue aims to gather cutting-edge research and authoritative reviews focused on the identification, validation, and mechanistic characterization of novel biomarkers, including metabolomic, lipidomic, and redox biomarkers, and therapeutic targets for human neurodegenerative diseases. We particularly encourage contributions that integrate untargeted and targeted metabolomics/lipidomics with other modalities (e.g., proteomics, transcriptomics, neuroimaging, or iPSC models) to uncover metabolic vulnerabilities, define disease subtypes, or evaluate therapeutic responses. Submissions spanning fundamental mechanistic studies, translational research, computational modeling of metabolic networks, preclinical target evaluation, metabolomic biomarker discovery and validation, and early-phase clinical investigations are all welcome. By integrating multidisciplinary approaches across molecular neuroscience, metabolomics, biomarker science, therapeutics development, and clinical neurology, this Special Issue seeks to accelerate the development of transformative strategies for early diagnosis, disease monitoring, and targeted intervention. Ultimately, our goal is to highlight innovative research that will contribute to a deeper mechanistic understanding and advance the next generation of neuroprotective therapies for patients suffering from debilitating neurodegenerative disorders.

Keywords: Neurodegenerative diseases, biomarkers, therapeutic targets, neuroprotection, molecular mechanisms, precision medicine, metabolomic, neuroinflammation, protein aggregation