Emerging roles of lipocalin-2-mediated neuroimmune interactions in chronic pain and itch.

Neuroimmune interactions serve as a core regulatory node of chronic pain and pruritus and a key target for clinical intervention. Lipocalin-2 (LCN2), a member of the lipocalin superfamily, is a multifunctional protein widely expressed in various tissues and cells. LCN2 exerts diverse biological effects by regulating iron metabolism, mediating inflammatory responses, and participating in signal transduction pathways. In recent years, accumulating evidence has indicated that LCN2 plays a crucial role in the pathogenesis of chronic pain and pruritus through neuroinflammation, neuron-glia interactions, and modulation of neural signaling. In chronic pain, LCN2 contributes to the development and maintenance of inflammatory pain, neuropathic pain, morphine tolerance, and thalamic pain by disrupting iron homeostasis, inducing oxidative stress, and promoting central sensitization. For chronic pruritus, LCN2 modulates the excitability of pruritus-related neurons via pathways such as the IL-6/STAT3 axis, and participates in the pathological processes of pruritus in allergic contact dermatitis, xerosis, atopic dermatitis, and psoriasis. This review summarizes the structural characteristics, physiological functions of LCN2, and its specific mechanisms in regulating chronic pain and pruritus, and further discusses the potential therapeutic value of targeting LCN2, aiming to provide a theoretical basis for the development of novel interventions for chronic pain and pruritus.