{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:38:14Z","timestamp":1792175894055,"version":"4.4.0"},"reference-count":209,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Neurodegenerative disorders, including Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), Huntington\u2019s disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial\u2013ROS\u2013inflammatory signaling, aggregation\u2013proteostasis failure, synaptic\u2013neuroimmune dysfunction, and gut\u2013brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP\u2013AMP synthase (cGAS)\u2014stimulator of interferon genes (STING) pathways\u2014play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood\u2013brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles.<\/jats:p>","DOI":"10.3390\/cells15110962","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T15:05:08Z","timestamp":1779721508000},"page":"962","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Polypharmacology of Pathway Crosstalk in Neurodegenerative Diseases: Chemical Modulation of Interconnected Signaling Networks"],"prefix":"10.3390","volume":"15","author":[{"given":"Muhammad Sohail","family":"Khan","sequence":"first","affiliation":[{"name":"College of Korean Medicine, Gachon University, 1342 Seongnamdaero, Seongnam 13120, Republic of Korea"},{"name":"Department of Cellular and Integrative Physiology, School of Medicine, University of Texas, Health Science Center at San Antonio (UTHSCSA), 7703 Floyd Curl Dr., San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9246-0850","authenticated-orcid":false,"given":"Imran","family":"Zafar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology, Faculty of Science, The University of Faisalabad (TUF), Faisalabad 38000, Punjab, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2595-9992","authenticated-orcid":false,"given":"Muhammad","family":"Noman","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences and Medicine, The University of Faisalabad (TUF), Faisalabad 38000, Punjab, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabsik","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Korean Medicine, Gachon University, 1342 Seongnamdaero, Seongnam 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki Sung","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Korean Medicine, Gachon University, 1342 Seongnamdaero, Seongnam 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3667-5790","authenticated-orcid":false,"given":"Jean C.","family":"Bopassa","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology, School of Medicine, University of Texas, Health Science Center at San Antonio (UTHSCSA), 7703 Floyd Curl Dr., San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s11011-021-00800-w","article-title":"Neurodegenerative disorders of alzheimer, parkinsonism, amyotrophic lateral sclerosis and multiple sclerosis: An early diagnostic approach for precision treatment","volume":"37","author":"Pathak","year":"2022","journal-title":"Metab. 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