Advances in research on the pathogenesis and signaling pathways associated with postoperative delirium (Review)

Postoperative delirium (POD) is a common postoperative complication, characterized by acute, transient and fluctuating declines in consciousness and attention, with an incidence that increases with age. POD is associated with various adverse postoperative outcomes, including prolonged hospital stays, higher medical costs and increased morbidity and mortality rates. Moreover, it has been suggested that POD, as an early manifestation of postoperative cognitive impairment, may serve as a precursor to long‑term cognitive dysfunction. Given its considerable clinical impact, the prevention and management of POD are of critical importance. However, the mechanisms underlying POD remain insufficiently understood. Current hypotheses primarily implicate neuroinflammation, oxidative stress, neurotransmitter dysregulation and pathological protein changes, such as β‑amyloid deposition and tau hyperphosphorylation. Disruptions in the sleep‑wake cycle, electroencephalographic burst suppression, the microbiota‑gut‑brain axis, the olfactory‑brain axis and genetic susceptibility to delirium may also contribute to POD occurrence. Multiple signaling pathways are involved in POD, including the Wnt/β‑catenin, PI3K/AKT, brain‑derived neurotrophic factor/tropomyosin receptor kinase B, toll‑like receptor and NF‑κB pathways. These findings not only elucidate potential mechanisms but also highlight essential therapeutic targets and theoretical foundations for clinical management. However, due to the complexity and multifactorial nature of the pathogenesis of POD, no comprehensive or widely accepted clinical measures have yet been established for its prevention and treatment. Both non‑pharmacological and pharmacological interventions have a role in POD prevention and treatment. Non‑pharmacological strategies are currently prioritized, such as cognitive training, the Hospital Elder Life Program and comprehensive geriatric assessment. Pharmacological interventions include dexmedetomidine, melatonin and non‑steroidal anti‑inflammatory drugs, with intranasal insulin emerging as a promising preventive approach. Additionally, anesthesia management strategies, including depth of anesthesia monitoring, blood pressure regulation and multimodal postoperative analgesia, have also been recognized as effective measures for reducing the risk of POD. The present review provides a comprehensive overview of the pathogenesis of POD, relevant signaling pathways and available preventive and therapeutic strategies. By deepening the understanding of POD, the present review aims to offer practical guidance for clinicians in optimizing prevention and management approaches.