Chronic pain: from central sensitization to network homeostasis imbalance

Following a "mechanism-technology-translation" framework and focusing on high-quality studies published between 2023 and 2025, this review critically synthesizes representative findings on network-level remodeling in central sensitization, the neuroimmune axis, energy metabolism and mitochondrial homeostasis, epigenetic reprogramming, and clinical translation in chronic pain. The onset and maintenance of chronic pain involve multi-level coupling among neurons, glial cells, the immune system, and epigenetic regulatory mechanisms. The core pathological feature can be characterized as the deviation of pain-regulatory networks from their normal functional range across molecular, cellular, and circuit levels, resulting in a self-sustaining abnormal steady state-termed "network homeostasis imbalance. " Major bottlenecks include the absence of integrative network-level pathological models, systematic discrepancies between animal models and clinical phenotypes, insufficient cross-cohort reproducibility of biomarkers, and inadequate translational pathways from basic discoveries to clinical validation. Chronic pain research and management need to shift from a "single-target, single-pathway" paradigm toward network-level systems analysis. Establishing actionable linkages among mechanistic analysis, technological validation, and clinical implementation is key to advancing chronic pain management from empirical analgesia toward precision intervention.