Ya-Qun Zhou

Ischemia-Reperfusion Injury (IRI) is a prototypical sterile inflammatory process that complicates solid-organ transplantation, reperfusion therapy for acute myocardial infarction, and revascularization procedures. Clinical management relies largely on supportive and procedural measures; no specific targeted therapy is available. Interleukin-33 (IL-33), a multifunctional member of the IL-1 cytokine family, is constitutively localized to the nucleus in several structural cell types and acts extracellularly as an alarmin after release. The IL-33/ST2 signaling axis has been implicated in multiple phases of IRI. This review describes the conserved core of the IL-33/ST2 signaling cascade. It also examines the regulatory mechanisms and functional heterogeneity of IL-33 across six major IRI-susceptible organ systems: the cardiovascular system, kidney, liver, lung, brain, and gastrointestinal tract. Available evidence suggests a recurrent but not universal pattern: IL-33 can amplify acute sterile inflammation in some organs and models, yet support inflammation resolution and tissue repair in other settings or at later stages. The effects of IL-33 depend on the organ involved, the cellular source of IL-33, the spatial distribution of ST2-expressing target cells, the local microenvironment, and the phase of injury and timing of intervention. This review summarizes recent preclinical advances in IL-33/ST2-targeted strategies and discusses the principal challenges to their clinical translation. These include limited human efficacy and safety data, the lack of clinically feasible intervention strategies, and the absence of validated companion biomarkers. The IL-33/ST2 axis may be an organ- and context-specific therapeutic target for IRI, but further validation is required before clinical application.

Although the underlying mechanisms of renal IRI have been extensively studied, the corresponding effective treatments are still lacking. HMGB1, an important nuclear factor that is secreted outside cells when experiencing stress conditions, acts as a DAMP and exerts crucial effects on renal IRI. Many studies have suggested that the effect of HMGB1 on kidney damage is mediated mainly through the interaction of HMGB1 with pattern recognition receptors such as TLR4 and RAGE, which then results in the aggravation of local inflammatory response, increased infiltration of leukocytes, and finally renal tubular damage. Preclinical studies using animal models have demonstrated that inhibition of HMGB1 and downstream signal pathways can attenuate renal injury. This review critically evaluates HMGB1 in renal IRI across redox state, subcellular localization, temporal and cell-specific release, receptor usage, integrated stress pathways, autophagy, and regulated cell death. It also compares direct neutralization, inhibition of release or translocation, epigenetic/RNA-based regulation, and receptor-directed strategies. The evidence is predominantly derived from short-term rodent studies, with one large-animal antibody study and no therapeutic human trials. Accordingly, HMGB1 is best regarded as a biologically compelling but clinically unvalidated target whose therapeutic value will depend on redox- and phase-selective inhibition, kidney-directed delivery, and rigorous pharmacokinetic and safety evaluation.

Importantly, chronic pain is no longer regarded only as a symptom secondary to tissue injury or disease, but is considered rather as a complex condition that may involve persistent maladaptive changes in nociceptive processing, affective regulation, and behavior (3). Although substantial progress has been made in defining nociceptive processes and pain neuroanatomy, effective treatment is still limited by the heterogeneous nature and poor understanding of the mechanisms behind the onset, maintenance, modulation, and remission of pain experience. In this regard, the Research Topic "Insights into Pain Mechanisms -2024/2025" has been created to provide recent advances in pain neurobiology, particularly focusing on molecular pathways, neuroimmune interactions, brain circuits, translational approaches, and innovative technologies that can be useful in mechanism-based and personalized pain management.The five articles featured within this Research Topic represent the range of current research into mechanisms of pain. Together, they move across levels of analysis, from intracellular stress signaling and transcriptomic responses to descending brainstem modulation, multidimensional clinical phenotyping, and artificial intelligence (AI)supported approaches with potential relevance to precision pain management. Such an integrative approach is especially appropriate in light of the fact that recent advances in the field of pain emphasize the importance of a multimodal approach which addresses biological mechanisms as well as brain-behavioral aspects of pain perception and disability (4). The importance of studying mechanisms of pain is not only relevant to developing drugs, but non-pharmacological interventions as well.Alshahrani and Reddy examined the relationship between pain measures of various dimensions and balance control in community-dwelling older adults. By integrating pressure pain threshold, pain intensity, pain catastrophizing, posturographic parameters, and functional reach performance, their study showed that not only the sensory but also cognitive-affective aspects of pain are independent predictors of postural instability.Chronic pain was linked to reduced functional reach, and longer pain duration predicted greater sway area. These findings take pain mechanism studies beyond the study of sensory processing alone and highlight how persistent pain can affect motor control, risk of falls, and functional independence in older adults.Chen et al. investigated the mechanism of electrothermal acupuncture in a model of postherpetic neuralgia in rats induced by resiniferatoxin. Electrothermal acupuncture enhanced mechanical withdrawal thresholds, reduced pro-inflammatory cytokines, inhibited reactive oxygen species production, and modulated ATP abnormalities in peripheral and spinal tissues. Moreover, the transcriptomic profiling indicated the candidate genes involved in type I interferon-mediated innate immune pathways, including Mx1, Irf7, Rtp4, Oasl2, and Ifit1bl as central genes. These findings suggest that electrothermal acupuncture may influence neuropathic pain through coordinated regulation of neuroinflammatory, oxidative, metabolic, and innate immune-related pathways.summarizing existing primary literature data on the brain and spinal cord in pain modulation. Their review reinforces the critical involvement of the periaqueductal gray and rostral medulla, and also demonstrates that cortical and limbic regions (prefrontal, anterior cingulate, insular, and amygdala) are involved in the pain processing pathway in a context-dependent manner. Moreover, they also demonstrate that cognitive and emotional processes, such as distraction, imagery, catastrophizing, and anxiety, can modify the pathway of descending pain regulation through altered connectivity between the cortex and brainstem. These findings underscore the importance of studying human pain modulation directly and may inform the rational development of therapeutic approaches such as transcranial direct current stimulation and spinal cord stimulation. Uckac et al. provided a comprehensive translational approach to chronic pain by incorporating genetics, brain imaging, digital phenotyping, and AI. Their review reveals chronic pain as an independent medical condition influenced by the interplay of biological, psychological, and social factors. Genetic overlaps with psychiatric disorders and the immune system, disturbances in the prefrontal, insula, and limbic regions, as well as the use of wearables and AI, are pointed out by the authors as potentially beneficial elements that will be helpful in the objective monitoring and management of patients in the future. This contribution illustrates how mechanisminformed stratification may help move pain care beyond symptom reporting toward data-driven precision medicine. Niu et al. emphasized endoplasmic reticulum stress as a potential target for treatment of neuropathic pain. Their review provides an insight into how the chronic activation of the unfolded protein response, mediated by PERK, IRE1α, and ATF6 signaling, leads to neuroinflammation, oxidative stress, ferroptosis, and dysfunctional neuron-glia interaction. Importantly, they discuss the specificity of endoplasmic reticulum stress in the different types of cells, such as immune cells, sensory neurons, and oligodendrocytes. This cell-specific perspective provides a useful framework for developing targeted interventions that modulate pathological stress signaling without disrupting adaptive homeostatic responses.Collectively, these articles demonstrate that pain mechanisms cannot be understood through a single pathway, tissue, or discipline. Rather, pain arises from the interaction between peripheral nociceptor input, immune and metabolic signals, glia and neurons, descending control pathways, cognitive affective factors, and a greater clinical context.A shared message across the collection is that mechanism-based pain...

Collapsin Response Mediator Protein 2 (CRMP2) has emerged as a central node in the pathogenesis of chronic pain, functioning as a multimodal ‘molecular switch’ that regulates microtubule dynamics, ion channel trafficking, and synaptic plasticity. The dysregulation of CRMP2, particularly through aberrant post-translational modifications (PTMs) such as phosphorylation and SUMOylation, is a critical driver of both peripheral and central sensitization. This review systematically examines the structure, regulation, and multifaceted roles of CRMP2 in pain signaling pathways. We then critically evaluate a spectrum of CRMP2-targeted therapeutic strategies, including small-molecule inhibitors, peptide-based agents, and gene silencing, highlighting their promising preclinical efficacy and safety profiles. Despite challenges in targeting specificity and central nervous system delivery, we posit that innovations in delivery systems, precision medicine, and AI-assisted drug design will catalyze the clinical translation of CRMP2-based, non-opioid analgesics, offering a paradigm shift in chronic pain management.

Background: Advanced cancer patients still suffer from devastating bone pain, with less efficacious treatments. The spinal microglia activation and neuroinflammation are the pivotal pathological processes of cancer‐induced bone pain (CIBP). This study aims to explore whether c/EBPβ negatively regulates CD200R1 to induce microglia‐medicated neuroinflammation in the spinal cord of CIBP mice. Methods: The CIBP mice model was constructed by intrafemoral injection of Lewis lung cancer cells to investigate the role of CD200/CD200R1 signaling and their upstream molecule CCAAT/enhancer binding protein β (c/EBPβ) in CIBP. Mechanical allodynia and thermal hyperalgesia were evaluated by von Frey filaments and hot plate, respectively. Adeno‐associated viruses were constructed to regulate the expression of CD200R1 and c/EBPβ. The protein level was assessed by western blotting, and microglia activation was detected by immunofluorescence. Results: Our results showed that CD200/CD200R1 signaling was inhibited in the spinal cord of CIBP mice. Intrathecal injection of CD200R1 agonist CD200Fc effectively reversed the nociceptive behaviors in CIBP mice. Overexpression of CD200R1 could also effectively ameliorate the pain behaviors and spinal neuroinflammation in CIBP mice. Transcription factor c/EBPβ was upregulated in the spinal cord of CIBP mice. Knockdown of c/EBPβ effectively inhibited the microglia‐mediated neuroinflammation by restoring CD200R1 protein levels, alleviating pain behavior in CIBP mice. Conclusion: c/EBPβ‐mediated suppression of the CD200/CD200R1 signaling pathway represents one potential mechanism in promoting microglial activation and neuroinflammation in the spinal cord of CIBP mice, which provides a potential therapeutic target for CIBP management.

 Chronic pain is an atypical pain condition that imposes a significant personal and economic burden. Current medications for chronic pain offer only temporary relief to a subset of patients and may lead to considerable adverse effects. Naringenin, a dihydroflavonoid categorized as a flavone, exhibits a broad spectrum of pharmacological activities and holds significant promise for chronic pain management. Extensive research has demonstrated that naringenin possesses analgesic effects across various chronic pain models. This review explores the molecular mechanisms and functions of naringenin in the management of chronic pain. It achieves this by reducing neuroinflammation and oxidative stress, as well as modulating matrix metalloproteinases (MMPs), ion channels in nociceptive terminals, and various intracellular signaling pathways, including the calcitonin gene-related peptide (CGRP) signaling pathway and the NO-cGMP-PKG-ATP-sensitive potassium channel signaling pathway. The established safety based on current preclinical evidence and multimodal mechanisms of naringenin enable multimodal therapeutic strategies targeting chronic pain pathogenesis networks.