Chronic pain patients experience more work disability leading to unemployment and major individual, societal and economic burden. Implanted neurostimulation has proven good results in terms of pain relief for chronic pain patients. As new stimulation techniques, paradigms and targets are being researched, a comprehensive synthesis of the effects of implanted neurostimulation on occupational outcomes remains undetermined. MEDLINE (via PubMed), Embase, Scopus & Web of Science were systematically searched. Risk-of-bias was assessed using the modified Downs & Black checklist. Random-effects meta-analyses, including a Bayesian approach, were conducted to provide estimates of work status and return to work rates. The study protocol was prospectively registered on PROSPERO (CRD42024501152). 67 studies were identified for inclusion in the review; 56 were included in the meta-analysis. The paired odds to work following neurostimulator implantation increased significantly (OR 5.17; 95%CI 2.89-9.23; I2=49.0%; n = 56; P < 0.0001) and were confirmed in the conservative random-effects (OR 3.39; 95%CI 2.00-5.75; n = 56; P < 0.0001) and Bayesian model with uniform prior (OR 5.68; 95%CI 3.08-11.79; n = 56). The pooled estimate for the proportion of patients returning to work across neurostimulation modalities was 26.05% (95%CI 20.73%-32.18%; I2=68.9%; n = 55). Implanted electrical neurostimulation is associated with increased paired odds to work and enabled chronic pain patients to return to work. The best effects were achieved following peripheral nerve stimulation and in patients suffering head-related pain.
Transcranial electrical stimulation (tES), including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), is considered a safe method to modulate cortical activity and endogenous brain oscillations. Given the therapeutic potential of tES across various clinical conditions and the central role of sleep in restoration and memory consolidation, numerous studies have investigated its effects on sleep and sleep-related parameters, yielding inconsistent results. This systematic review provides an up-to-date synthesis of 51 studies assessing the impact of tES on objectively measured electrophysiological sleep outcomes in both healthy individuals and clinical populations. The reviewed studies demonstrate heterogeneous effects, reflecting substantial variability in study designs. Nonetheless, consistent trends emerge, including reduced NREM1 and increases in total sleep time, NREM2, and NREM3 following tES. Moreover, slow-oscillatory tES increased slow-wave power during sleep. Here we show that tES, particularly slow-oscillatory tES, may positively influence sleep architecture and continuity by modulating endogenous brain oscillations. However, due to heterogeneous stimulation protocols, inconsistent findings, the limited number of significant effects and substantial risk of bias the current evidence remains inconclusive. Well-designed, large-scale trials targeting specific sleep outcomes are needed to clarify the therapeutic potential of tES.
Transcranial direct current stimulation (tDCS) has potential as a treatment for adult depression, but its effectiveness in adolescents remains unexplored. This study evaluated the feasibility, safety, and efficacy of tDCS in young in-patients with depression. In a randomized, double-blind, sham-controlled trial, 34 adolescent in-patients (mean age 15.48 years) received ten sessions of either tDCS or sham stimulation over two weeks, alongside standard treatment. Depression severity, quality of life, emotional and behavioral issues, and executive functions were assessed before, immediately after, and two weeks post-treatment. The results indicated that tDCS was feasible and well-tolerated, with 28 patients completing at least eight sessions. Side effects were reported in nearly half of the sessions (45% sham, 48% tDCS), primarily mild to moderate, and no sessions were interrupted due to discomfort. Both groups experienced significant improvements in depressive symptoms and high treatment satisfaction, but no significant differences were found between the tDCS and sham groups. In conclusion, while tDCS appears to be a safe treatment option for adolescents with depression, this study could not show it to be superior to sham treatment. Further research with greater statistical power is needed to control for covariates.
Deep Brain Stimulation (DBS) is an established treatment for advanced Parkinson's disease (PD), yet registry-based data from developing countries remain limited. This study reports the establishment and feasibility of the Iranian Deep Brain Stimulation Registry for Parkinson's Disease (IDBSR-PD). We conducted a single-center feasibility study at the Research Center for Neuromodulation and Pain, including all PD patients undergoing DBS implantation since 2014. Primary feasibility outcomes included patient enrollment coverage, follow-up adherence, data completeness, multidisciplinary implementation, and the sustainability of technical infrastructure. Secondary outcomes included descriptive patient characteristics. Only descriptive statistics were performed; no hypothesis testing or longitudinal outcome analyses were conducted. A total of 208 patients were enrolled (65.4% male; mean age 58.4 ± 10.2 years). Enrollment increased progressively over time, peaking in 2024 (n = 41). Patients were referred from multiple provinces across Iran. Data validation mechanisms and regular surveillance ensured acceptable data completeness. The IDBSR-PD demonstrates the feasibility and sustainability of a web-based DBS registry in a developing country. These findings confirm the viability of structured data collection and provide a foundation for future multicenter and longitudinal outcome research.
The recovery of motor function in patients with ischemic stroke is closely related to the plastic remodeling of cortical functional networks. Low-intensity transcranial ultrasound stimulation (TUS) has been shown to improve motor behavior in patients with ischemic stroke and modulate cortical functional networks in healthy individuals. However, whether motor improvement after TUS is associated with cortical functional network reorganization remains unclear. Therefore, in this study, we constructed a mouse model of ischemic stroke using male C57BL/6 mice and simultaneously recorded the local field potential and gait behavior data of the whole-brain cortex of mice in a free-walking state before and after ultrasound intervention. Gait parameters, cortical functional network connectivity, and topology were systematically analyzed, and the correlations between behavioral indicators and network connectivity were explored. Our findings revealed that TUS significantly improved motor function in the mouse model, modulated cortical functional network connectivity to restore it to a healthy state, enhanced global information integration ability, optimized local separation efficiency, and restored gait phase transition control. Furthermore, the TUS-induced changes in the cortical functional network were positively correlated with behavioral improvement. This study confirmed that motor improvement after low-intensity TUS is accompanied by cortical functional network reorganization, and that such reorganization may contribute to post-stroke functional recovery.Significance Statement Stroke disrupts the neural networks essential for maintaining gait coordination. Although low-intensity TUS stimulation can improve post-stroke motor performance, how it remodels and restores cortical functional network connectivity during natural behavior remains unclear. This study combined free-walking gait with simultaneous acquisition of cortical local field potentials to conduct a 7-day targeted ultrasound modulation intervention in the infarct area in ischemic stroke mice. Results showed that TUS significantly improved gait and induced gait-phase-specific cortical functional network connectivity reconnection. This study provides evidence for the neural mechanisms by which ultrasound promotes post-stroke motor function recovery and offers a theoretical basis for the translational application of TUS in stroke treatment.
Children with severe self-injurious behaviour (SIB) are at risk of permanent injury and lack effective treatment options. Neuromodulation of the nucleus accumbens (NAc), a key node in reward and behavioural regulation circuits, may directly modulate the drivers of SIB. We report long-term outcomes from a first-in-human, single-centre trial of deep brain stimulation (DBS) targeting the NAc in children and adolescents with profound autism and treatment-refractory SIB (NCT03982888). Six participants (ages 7-14 years; mean 11.7) underwent bilateral implantation and were followed prospectively for at least 24 months (mean 32.5 months, range 25.8-56.0). One serious adverse event occurred: a device-related infection requiring hardware explantation, followed by relapse to baseline levels of self-injury. Subsequent re-implantation in this participant yielded rapid improvement in SIB, providing single-subject, causal withdrawal-rechallenge evidence of treatment-specific benefit. Across the cohort, NAc-DBS produced sustained reductions in SIB frequency and severity, repetitive and obsessive-compulsive behaviours, and clinically meaningful improvements in quality of life. The durability of these effects over multi-year follow-up suggests that circuit-targeted neuromodulation may modify the developmental course of severe behavioural pathology. These findings provide the first long-term evidence that modulation of reward circuitry can durably alter maladaptive behaviour in childhood neurodevelopmental disorders.
Knee osteoarthritis (KOA) is a common degenerative bone disease, and transcutaneous electrical nerve stimulation (TENS) is an alternative and complementary therapy (ACM). This study revealed the role of TENS in regulating the intestinal microbiota in KOA rats. This study concentrated on the intestinal microbiota of KOA rats which were treated with TENS for 1, 2, and 3 weeks. Three intensities of TENS were used to treat KOA rats, and the expressions of IL6/8, PI3K-AKT were measured. The intestinal microbiota was analyzed by 16 S rDNA sequencing. Compared with the Model Control group, TENS could improve symptoms of KOA rats and inhibit the expressions of IL6/8 by down-regulating the PI3K-AKT expression. After 3 weeks of treatment with TENS, compared with the Model Control group, the abundances of Bacteroidetes, Bacteroidetes, and Thermodesulfobacteria increased in the TENS groups; the abundances of Ficmicutes, Campylobacter, and Verruca decreased in the TENS groups. TENS could improve the histomorphology of knee and inhibit inflammation in KOA rats. After treatment with TENS, the intestinal microbiota gradually changed from 1,2,3 weeks and the abundance of them was different with three intensities of TENS. Further study will elucidate the underlying mechanisms of TENS in altering gut microbiota and the potential therapeutic applications of these intestinal microbiota for KOA.
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Faecal incontinence (FI) increases up to 50% with age in institutionalized older individuals, and treatment options have been scarcely studied for older people. Posterior tibial nerve stimulation (PTNS) is a minimally invasive second-line treatment available. This research aims to assess long-term clinical outcomes of PTNS using the Wexner score in community-dwelling patients aged > 65 years, and its impact on quality of life (QoL). A prospective cohort study with 61 patients (median age 71 years; 79% women) was conducted. PTNS was administered in three phases over 12 months, with follow-ups (FUs) at 3, 6, 12 and 36 months. Optimal responders (ORs) were defined as achieving a > 50% reduction in Wexner score compared with baseline. Partial responders that presented a 25-50% reduction in Wexner score were also considered as potential long-term ORs. At the end of treatment, 64% of patients were OR, with sustained improvement in 77% of them at 36 months. Wexner score significantly decreased throughout FUs, from median ten to four (p < 0.001). Faecal incontinence quality of life questionnaires (FIQLs) showed limited improvement in depression domain at 6- and 36-month FUs. Faecal urgency improved in a logistic regression analysis (p < 0.01). Multivariable logistic regression identified increasing age as independently associated with clinical response (p = 0.04). PTNS was associated with improvement in incontinence severity scores and faecal urgency in selected community-dwelling older adults, although reductions in FI episode frequency and quality of life measures were limited. These findings suggest that PTNS may have a selective role within individualized management strategies, particularly in urgency-predominant symptoms. NCT05016453, retrospectively registered in 2021.
To provide an evidence-based framework for healthcare professionals to use neuromodulation technologies to restore neuromuscular function and relieve pain. An expert panel, convened by the American Academy of Pain Medicine Foundation, conducted a literature review of English-language studies published between 2015 and 2025 using PubMed, the Cochrane Library, Web of Science, and Scopus (detailed in Supplement 2). The panel screened abstracts, extracted key data, and evaluated evidence quality using a modified United States Preventive Services Task Force criteria. A Delphi process was used to achieve expert consensus on clinical recommendations for various neuromodulation technologies: Artificial intelligence-guided and robotic rehabilitation systems, virtual/augmented reality interfaces, brain-computer interfaces, electrical nerve stimulation (encompassing peripheral nerve stimulation transcutaneous electrical stimulation), vagus nerve stimulation, multifidus neurostimulation, surgery (eg,, regenerative peripheral nerve interface), scrambler therapy, spinal cord stimulation for motor restoration, and transcranial magnetic stimulation. The panel provided clinical recommendations and discussed mechanisms of action, evidence, and clinical considerations for each intervention. Evidence for these technologies is evolving, with some showing promising results in areas like improving upper limb function post-stroke, improving functional spine-related outcomes, and reducing chronic pain. Neuromodulation technologies offer a promising approach for neuromuscular restoration, focusing on interventions that promote functional recovery rather than solely providing symptomatic care. Areas for future research include more high-quality, large-scale studies with consistent outcome measures.
Neuromodulation is a standard therapy for bladder symptoms such as overactive bladder. Previous studies have demonstrated that non-continuous stimulation (NCS) can increase bladder capacity and that bladder pressure can be estimated from dorsal root ganglia (DRG) neural activity in anesthetized animal models. Our goal is to determine if NCS elicits similar bladder capacity effects as continuous stimulation (CS) and if bladder pressure can be estimated from DRG signals in an awake, unrestrained animal model. We performed aseptic, chronic implant surgeries with seven adult, male felines. Three animals were used to establish procedures, three for experimental testing, and one did not yield data. Bipolar stimulating electrodes were placed on the pudendal nerve and sacral nerve on the same side. Microelectrode arrays were inserted in two ipsilateral sacral DRG. Two single-lumen catheters were implanted in the bladder dome for recording bladder pressure and infusing saline. Fixed-sequence, repeated bladder fills were performed in four awake felines to evaluate the bladder capacity during no-stimulation (NS), NCS, and CS at either the pudendal or sacral nerve. NCS was performed based on increases in bladder pressure estimated from DRG recordings or when 50% of the average NS bladder capacity was reached. We observed similar bladder capacity increases for NCS (122 ± 31% of NS control) as for CS (121 ± 33%) in the four animals. NCS paradigms reduced stimulation time by 46% on average. Median correlation coefficients of 0.46 and 0.64 (maximum 0.93) between the predicted and measured bladder pressure were obtained for awake trials with DRG bladder units in two animals. This study demonstrated the feasibility of using NCS to increase bladder capacity in awake, unrestrained felines and for decoding bladder pressure from DRG recordings. Further studies are needed to optimize NCS timing for clinical translation.
Objective
Deep brain stimulation (DBS) for neuropsychiatric disorders increasingly relies on patient personalized approaches. One strategy to identify viable targets for personalized stimulation and biomarker detection uses a temporary, inpatient stereoelectroencephalography (sEEG) trial to identify optimal targets for permanent re-implantation. However, this approach reasons that neural signals are stable between repeated intracranial electrode implants, which is not yet validated.

Approach
We characterize the spectral stability of local field potentials after electrode reimplantation from an ongoing single-center clinical trial using two-staged sEEG/DBS for chronic pain (NCT04144972).

Main Results
Repeat neurosurgical implant of intracranial electrodes reliably targeted intended trajectories across staged surgeries occurring months apart (2.1 ± 1.2 mm Euclidean distance across 17 brain targets, 5 participants). Anatomical targeting error was correlated with differences in recorded electrophysiological power spectra between stages (r(15) = 0.51, p = 0.03). This correlation was stronger for the subset of regions re-targeted exclusively for biomarker sensing (r(6) = 0.73, p = 0.04), and non-significant for therapeutic stimulation sites (r(7) = .23, p = 0.76). Similarly, a multiple regression model significantly predicted spectral distance (F(4, 13) = 5.99, p = 0.008, adjusted r = 0.70) with an interaction between electrode type and Euclidean distance (t (13)= 2.39, p = 0.03).

Significance
Chronic intracranial EEG signals recapitulated temporary recordings in 17 of 17 brain regions with the major spectral peak within 1 Hz. Our results demonstrate the temporal stability of neural signals across months and validate the use of a two-staged intracranial EEG approach for chronic DBS sensing in humans.
Current research indicates that Virtual Reality (VR) can serve as an effective tool for evaluating and training postural control responses and its processing, to distorted sensory input. The aim was to evaluate posturographic spectral responses and adaptation to repeated visual VR-stimulation in young and older adults with wavelet analysis. Twenty-eight young (mean 25.3 years) and 25 older (mean 74.8 years) adults were included. Participants were standing on a force plate performing two control tests (eyes open and closed) and thereafter repeatedly watched a 120-second VR-simulation of a roller-coast ride five times. The first VR session produced a marked two-fold stability response: (1) significant spectral energy increased within 0.4-8.5 Hz in anteroposterior and lateral directions, and (2) significant spectral energy decreased within 0.03-0.13 Hz in anteroposterior direction. Older adults used significantly more high frequency energy and less low frequency energy. Repeated VR sessions significantly decreased high frequency energy in both groups. Wavelet analysis indicates that both younger and older adults employed similar spectral response patterns in response to immersive visual stimulation. However, older adults showed larger shifts in spectral characteristics, suggesting age-related differences in resilience. Postural control appeared capable of rapidly adapting to adjust biomechanical strategies and sensory weighting.
Poor ovarian response (POR) is associated with low ovarian reserve, which is commonly seen as a result of ovarian aging although it can be associated with genetic conditions, diseases, previous ovarian surgery, chemotherapy or toxic-related injury to the ovary. Despite pharmacologic advances, innovation in laboratory equipment and advances in embryo culture and selection, success rates in ART are hampered by age-related infertility, due to sociocultural trends favouring delayed childbearing attitudes. POR represents a challenging subgroup of patients, characterized by a low ovarian reserve and/or a suboptimal response to ovarian stimulation (OS). Different classification systems have been proposed to define POR, but none have proven useful to improve the clinical management of these patients. ART in these patients is associated with poor outcomes, significant psychological burden, and high drop-out rates after the first IVF attempt. No specific protocol has been proven better than the other in POR, and no drug to date has proven to increase the antral follicle pool. Advances in ovarian physiology have identified multiple follicular waves within a cycle, with continuous follicular recruitment. This opens the possibility of a multicycle approach, in which two or more consecutive stimulation cycles can be performed irrespective of the menstrual dates, with the aim of obtaining the desired number of oocytes necessary to obtain at least one euploid blastocyst. The multicycle approach increases the number of eggs and embryos available for transfer or vitrification, reduces time to pregnancy, and decreases drop-out rates. Non-pharmacological interventions to increase ovarian response like intraovarian PRP are still controversial and have not been proven effective in recent prospective randomized trials. Future directions and research on POR is discussed.
Bone disorders and skeletal defects represent a significant clinical challenge, often requiring transplantation techniques limited by donor site morbidity and insufficient regenerative potential. Tissue engineering and regenerative medicine (TERM) strategies using 3D bioprinting have emerged as promising alternatives, but their efficacy is limited by the difficulty of directing stem cell differentiation in a controlled and reproducible manner. To address this limitation, we are proposing 3D bone printing via ultrasound-mediated osteogenic differentiation of stem cells (referred to here as '3DBonUS'). This biofabrication approach integrates low-intensity pulsed ultrasound (LIPUS) with a microfluidic-assisted 3D bioprinting system. This unprecedented approach enables biophysical stimulation of human bone marrow stromal cells (HBMSCs) during the fabrication of scaffolds, promoting osteogenic differentiation without the need for extensive post-fabrication treatments. In addition, the incorporation of microbubbles (MBs) enhanced the effects of LIPUS by amplifying mechanical signals at the cellular level. Our results revealed that the 3DBonUS system significantly upregulated key osteogenic markers (RUNX-2, ALP, COL1A1, BMP-2, OCN and OPN) as confirmed by immunofluorescence and RT-qPCR analysis. Moreover, the LIPUS-treated constructs showed a significant (p<0.05) increase in alkaline phosphatase (ALP) activity and calcium deposition, indicating enhanced mineralisation. The biofabricated constructs maintained high cell viability while exhibiting improved osteogenic differentiation, surpassing traditional 3D bioprinting approaches in both efficiency and efficacy. The 3DBonUS strategy represents a new modality in skeletal TERM, combining biofabrication with targeted mechanical stimulation, with potential for scalability of scaffold manufacturing and clinical application. Future studies will aim to validate the functional skeletal scaffolds in vivo to assess their regenerative potential, with the goal of advancing patient-specific bone implants with enhanced osteogenic properties.
Myocardial infarction (MI) remains a major cause of heart failure, largely driven by maladaptive ventricular remodeling and excessive cardiac fibrosis. The IL-33/ST2L axis exerts cardioprotective and anti-fibrotic effects, but how the availability of the membrane receptor ST2L is controlled under stress conditions remains incompletely understood. Here, we investigated whether ubiquitin-proteasome-dependent turnover of ST2L, mediated by the E3 ligase Znrf2, constrains IL-33/ST2L signaling and promotes post-MI fibrosis. Using neonatal mouse cardiac fibroblasts, cycloheximide chase and pharmacological inhibition experiments revealed that ST2L is a short-lived protein degraded predominantly through the proteasome rather than the lysosome. IL-33 stimulation enhanced ST2L internalization and induced robust polyubiquitination, thereby accelerating proteasomal degradation. Candidate screening and gain-of-function analyses identified Znrf2 as a functional E3 ligase-associated regulator of ST2L turnover: Znrf2 overexpression selectively reduced ST2L, but not sST2, in a dose-dependent manner, whereas proteasome inhibition stabilized ST2L. Mapping experiments showed that the Znrf2 zinc-finger domain recognizes a 306-315 amino acid motif in ST2L, and deletion of this motif rendered ST2L resistant to Znrf2-induced degradation. In a mouse MI model, Znrf2 expression was upregulated in the infarcted myocardium, accompanied by increased collagen deposition. Systemic administration of the proteasome inhibitor MG-132 or cardiac-specific Znrf2 knockdown preserved ST2L, particularly at the plasma membrane, attenuated myocardial fibrosis, and improved echocardiographic indices of left ventricular function. Importantly, AAV9-mediated silencing of ST2L blunted the anti-fibrotic and functional benefits of MG-132 and Znrf2 knockdown, indicating that these interventions act, at least in part, through ST2L. Collectively, our data identify Znrf2-dependent ST2L ubiquitination and proteasomal degradation as a negative regulatory mechanism that limits IL-33/ST2L cardioprotection after MI. Targeting the Znrf2-ST2L axis to preserve functional ST2L may represent a promising strategy to restrain post-infarction cardiac fibrosis and remodeling.
The spatiotemporal organization of proteins and lipids within membranes is crucial for ensuring proper cellular signaling. While the segregation of proteins and lipids into membrane nanodomains is well established, it remains unclear whether nanodomains can generate gradients of small diffusible molecules. In plants, reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), act as key signaling molecules in response to environmental stimuli such as osmotic stress. However, how extracellular H2O2 affects intracellular signaling has remained unknown. Here, we show that osmotic stimulation induces the formation of localized, H2O2-rich nanoenvironments at the cytoplasmic face of the plasma membrane (PM) in Arabidopsis root cells. Using a PM-tethered H2O2 biosensor, we found that these oxidized nanodomains arise from the clustering of RESPIRATORY BURST OXIDASE HOMOLOGs (RBOHs) and RHO OF PLANTS 6 (ROP6), in coordination with aquaporin-mediated H2O2 transport via the PLASMA MEMBRANE INTRINSIC PROTEIN2;7 (PIP2;7). These local redox hotspots at the PM create a feedforward loop in which H2O2 enhances ROP6 nanoclustering, thereby amplifying ROS signaling. Disruption of H2O2 production or transport dampens both ROP6 clustering and anisotropic cell expansion, indicating a crucial role for spatially confined redox signaling in regulating plant growth under osmotic stress. Our findings propose a model in which ROP6/RBOHD-F/PIP2;7 nanodomains function as discrete redox signaling units, redefining ROS signaling at the PM as a structured, signal-specific, and compartmentalized process.
The hormone vasopressin (AVP) controls renal water reabsorption by modulating the expression and trafficking of the water channel aquaporin-2 (AQP2) through the activation of the cAMP/PKA signal transduction pathway. Previous studies revealed that Olive Leaf Extract (OLE) counteracts the vasopressin-dependent AQP2 functions by stimulating the calcium-sensing receptor (CaSR). Here, the biological activities of p-Coumaric acid, a selective polyphenol in OLE, were investigated. Stimulation of renal collecting duct MCD4 cells with p-Coumaric acid at a concentration of 1 nM caused a significant intracellular calcium release. NPS-2143, a selective CaSR antagonist, abolished this increase. Molecular docking analysis revealed that p-Coumaric acid can form binding interactions with the binding pocket of Tecalcet, a known CaSR activator, likely suggesting that p-Coumaric acid may stimulate the CaSR. Confocal analysis and immunoblotting experiments showed that p-Coumaric acid impaired the DDAVP-dependent membrane expression of AQP2 and the consequent increase of the osmotic water permeability (Pf). Additionally, Fluorescence Resonance Energy Transfer (FRET) experiments demonstrated that p-Coumaric acid prevented the DDAVP-induced cAMP generation, consequently attenuating the AQP2 phosphorylation at serine 256. Together, these findings suggest that p-Coumaric acid may antagonize the effects of vasopressin, possibly by binding to and stimulating the CaSR.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disorder characterized by vascular inflammation and the activation of neutrophils. Complement component 5a (C5a) is pivotal in neutrophil priming and ANCA-mediated activation. Although progranulin (PGRN) is recognized for its involvement in inflammatory processes, yet its specific role in ANCA-associated vasculitis (AAV) remains poorly understood This study investigates the functional interplay between PGRN and C5a in enhancing neutrophil activation in response to ANCA stimulation. Neutrophils were primed with recombinant PGRN and subsequently stimulated with myeloperoxidase (MPO)-ANCA or proteinase 3 (PR3)-ANCA-positive immunoglobulin G. The respiratory burst was evaluated through dihydrorhodamine oxidation, while degranulation was quantified by measuring lactoferrin release. Additionally, the effects of PGRN-neutralizing antibodies on C5a-primed neutrophils were evaluated. PGRN significantly upregulated membrane-bound proteinase 3 expression in neutrophils compared to untreated controls (368.0 ± 18.5 vs. 178.0 ± 14.7, p < 0.001) and enhanced MPO release in the culture supernatants (1462.8 ± 202.2 vs. 526.8 ± 118.8, p < 0.001). PGRN-primed neutrophils demonstrated increased respiratory burst activity (p < 0.001) and elevated lactoferrin release (p < 0.001) compared to non-primed cells. Inhibition of PGRN significantly diminished ANCA-mediated oxygen radical production (p < 0.001) and degranulation (p < 0.001) in C5a-primed neutrophils. PGRN functionally enhances C5a-mediated neutrophil activation, suggesting a cooperative effect but not a direct molecular interaction. This in vitro study using human neutrophils explores the cooperative effects of PGRN and C5a in ANCA-induced activation. Future research should investigate the use of PGRN inhibitors to mitigate inflammation in AAV.