EMERGING NETWORK BASED PHARMACOLOGY APPROACHES FOR SEQUENTIAL BLOCKADE OF SIGNALING PATHWAYS OF PERIPHERAL NEUROPATHY
Payal Gaur, Muskan, Arpit Kumar, Ajay Kumar Pal, Saahil Arora, Manish Yadav
Department of Pharmacy, School of Healthcare & Allied Sciences (SOHAS),
GD Goenka University, Sohna-Gurgaon Road, Sohna, Haryana – 122103, India
Abstract: The global burden of PN continues to increase owing to the rising prevalence of diabetes mellitus, cancer chemotherapy, metabolic disorders, autoimmune diseases, infections, and neurodegenerative conditions. Despite substantial progress in understanding the molecular basis of neuropathy, currently available pharmacotherapies primarily provide symptomatic relief and often fail to halt disease progression or promote nerve regeneration. One of the major limitations of conventional therapeutic approaches is their reliance on single-target interventions for a disease driven by multiple interconnected molecular networks. Recent advances in systems biology and network pharmacology have transformed the understanding of complex neurological disorders by enabling the identification of multitarget therapeutic strategies. Emerging evidence indicates that peripheral neuropathy evolves through a sequential activation of pathological signaling cascades involving oxidative stress, mitochondrial dysfunction, NF-κB-mediated neuroinflammation, NLRP3 inflammasome activation, ion-channel sensitization, apoptosis, and impaired neuroregeneration. These interconnected pathways collectively establish a self-sustaining cycle of neuronal injury and chronic pain. Consequently, therapeutic strategies capable of temporally targeting distinct signaling modules may provide greater efficacy than simultaneous or single-target inhibition. This review discusses the molecular pathogenesis of peripheral neuropathy and highlights recent developments in network pharmacology, artificial intelligence-assisted target identification, protein–protein interaction networks, molecular docking, and multi-omics integration. Furthermore, a novel framework of sequential pathway blockade is proposed, involving early suppression of oxidative stress pathways, subsequent inhibition of inflammatory and inflammasome signaling, modulation of nociceptive ion channels, and activation of neuroregenerative mechanisms. Particular emphasis is placed on phytochemical-based multitarget therapeutics capable of regulating ROS/Nrf2, NF-κB, NLRP3, TRPV1, SIRT1, and PI3K/Akt signaling networks. The integration of network pharmacology with precision medicine approaches may facilitate the development of next-generation therapeutics for peripheral neuropathy and establish a new paradigm for systems-based neuropharmacology.
Keywords: Peripheral neuropathy; Network pharmacology; Sequential blockade; NLRP3 inflammasome; TRPV1; Oxidative stress; Neuroinflammation; SIRT1; PI3K/Akt; Phytochemicals; Systems pharmacology.
VOLUME 10 ISSUE 07 2026: 423 – 435