Pulchinenoside B4 attenuates gouty arthritis by regulating NLRP3 inflammasome and macrophage polarization: a transcriptomics-based analysis.

Curcumin analogue AI-44 alleviates MSU-induced gouty arthritis in mice via inhibiting cathepsin B-mediated NLRP3 inflammasome activation

The pathogenesis of gouty arthritis (GA) begins with the deposition of monosodium urate (MSU) crystals in the joints. This crystal deposition triggers a critical inflammatory response by activating the NLRP3 inflammasome, which in turn drives the maturation and release of pro-inflammatory cytokines such as IL-1β. Beyond this well-defined inflammatory axis, metabolic dysregulation is increasingly recognized as a core component of GA pathogenesis. This paper systematically reviews the crosstalk between metabolic signaling and the NLRP3 inflammasome in GA, elucidating how MSU crystals serve as a bridge between hyperuricemia (HUA) and innate immune activation. Furthermore, we elaborate the dual role of metabolic factors: acting both as “primer” and “amplifiers” of NLRP3 inflammasome activation, significantly lowering its activation threshold. This mechanistic association offers novel therapeutic insights for GA management: synergistic regulation of metabolic signaling alongside targeted inhibition of NLRP3 inflammasome activation enables more effective therapeutic interventions. Defining gout as a “metabolic-inflammatory” disorder has led to the development of novel dual-target therapeutic strategies—simultaneously alleviating inflammatory symptoms while regulating metabolic abnormalities. Such approaches hold significant promise for effectively preventing and controlling gout attacks, whilst reducing the risk of long-term complications.

BackgroundGout is an inflammatory condition induced by the deposition of monosodium urate (MSU) crystals in joints and soft tissues, and it can lead to acute or chronic arthritis. MSU are pro-inflammatory stimuli that can initiate, amplify and sustain an intense inflammatory response. In this study, we evaluated the anti-inflammatory effect of an extract of Mollugo pentaphylla (MPE) on MSU-induced gouty arthritis in a mouse model.MethodAn MSU crystal suspension (4 mg/50 μL) was injected intradermally into the right paw. The mice were orally administered MPE (150 mg/kg or 300 mg/kg) or the positive control drug colchicine (1 mg/kg) 1 h before the MSU crystals were injected and then once daily for 3 days. The effects of MPE included inflammatory paw edema and pain upon weight-bearing activity, and we evaluated the inflammatory cytokine expression and paw tissue inflammation-related gene expression.ResultsMPE suppressed inflammatory paw edema and pain in the MSU-induced mice. MPE showed anti-inflammatory activity by inhibiting the production of TNF-α, interleukin (IL)-1β, NLRP3 inflammasome and NF-κB.ConclusionThese results suggest that MPE has potent anti-inflammatory activities and may be useful as a therapeutic agent against gouty arthritis.

Gouty arthritis is a common metabolic disorder characterized by the deposition of monosodium urate (MSU) crystals in joints. Aberrant activation of the NLRP3 inflammasome is a key driver of MSU-induced joint inflammation, making it a promising therapeutic target for gouty arthritis. Gnetum montanum Markgr. has long been used in traditional medicine in parts of Asia to treat gout; however, its effects on gout-specific inflammatory responses have not been fully elucidated. In this study, we used two cell models, including MSU-stimulated mouse primary peritoneal and THP1 derived macrophages, in combination with western blot analysis, enzymatic activity assays, ELISA method, and flow cytometry analysis to evaluate the protective effect of G. montanum extract (GME) against MSU-driven inflammation. A mouse model of MSU-induced paw edema was then employed to validate the in vivo anti-inflammatory efficacy. We found that GME alleviated gouty inflammation by inhibiting NLRP3 inflammasome activation in mouse peritoneal and human THP-1 macrophages. GME also protected macrophages from MSU-induced pyroptosis, a pro-inflammatory form of programmed cell death. Mechanistically, GME suppressed xanthine oxidase (XO) activation triggered by MSU crystals, resulting in decreased reactive oxygen species (ROS) production. This reduction in ROS prevented the upregulation of thioredoxin-interacting protein (TXNIP), a key mediator that binds to and activates NLRP3. Furthermore, oral administration of GME in mice attenuated MSU-induced paw inflammation, likely through downregulation of XO-driven oxidative stress and NLRP3 inflammasome signaling. These findings suggest that GME effectively modulates gout-specific inflammatory pathways and warrants further investigation of GME as a potential therapeutic candidate for gouty arthritis.

AB0075 Intraarterial injection of human adipose-derived mesenchymal stem cells (HAD-MSCS) attenuates inflammation in acute arthritis model

Persistent hyperuricemia can lead to the generation and deposition of monosodium urate (MSU) crystals. This can trigger gouty arthritis (GA), which in turn induces inflammation. Activation of the Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome plays a critical role in the onset and progression of GA. Autophagy may have a dual effect on GA with regard to the NLRP3 inflammasome. Therefore, the present study aimed to gain a deeper comprehension of the interaction between autophagy and NLRP3 inflammasome activation is imperative for developing more efficacious treatments for GA. Peripheral blood monocytes (PBMCs) were first isolated from GA patients and healthy controls and underwent bulk RNA sequencing analysis. Overexpression and knockdown of dual specificity phosphatase 1 (DUSP1) was performed in THP-1 monocytes to investigate its role in the immune response and mitochondrial damage. The luciferase assay and Western blot analysis were used to study the interaction between autophagy and NLRP3 inflammasome activation. Bulk RNA sequencing analysis showed significant upregulation of DUSP1 expression in PBMCs from GA patients compared to healthy controls. This result was subsequently verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR). DUSP1 expression in human THP-1 monocytes was also shown to increase after MSU treatment. Downregulation of DUSP1 expression increased the secretion of inflammatory cytokines after MSU treatment, whereas the overexpression of DUSP1 decreased the secretion levels. Lipopolysaccharides (LPS) combined with adenosine-triphosphate (ATP) led to mitochondrial damage, which was rescued by overexpressing DUSP1. DUSP1 overexpression further increased the level of autophagy following MSU treatment, whereas downregulation of DUSP1 decreased autophagy. Treatment with the autophagy inhibitor 3-Methyladenine (3-MA) restored inflammatory cytokine secretion levels in the DUSP1 overexpression group. MSU caused pronounced pathological ankle swelling in vivo. However, DUSP1 overexpression significantly mitigated this phenotype, accompanied by significant downregulation of inflammatory cytokine secretion levels in the joint tissues. This study revealed a novel function and mechanism for DUSP1 in promoting autophagy to mitigate the MSU-induced immune response in GA. This finding suggests potential diagnostic biomarkers and anti-inflammatory targets for more effective GA therapy.

Autophagy induced by PP121 alleviates MSU crystal-induced acute gouty arthritis via inhibition of the NLRP3 inflammasome

BackgroundGouty arthritis (GA) is a common inflammatory disease with pain caused by the deposition of monosodium urate (MSU) crystals into joints and surrounding tissues. Resveratrol (Res), derived from grapes and peanuts and the traditional Chinese medicine (TCM) Reynoutria japonica for GA, acts against oxidation and inflammation. The present study aimed to investigate the therapeutic effect and mechanism of Res on GA.MethodsArthritis rat models, MSU-induced peritonitis mouse models, and inflammatory models of mouse bone marrow-derived macrophage (BMDM) were used in this study. Enzyme-linked immunosorbent assay (ELISA), JC-1, histopathological, immunofluorescence, flow cytometry, Western blot methods were applied to observe the effects of resveratrol on NLRP3 inflammasomes and mitophagy.ResultsRes significantly improves the gait score and synovitis of rats with GA and inhibits the peritoneal inflammation induced by MSU. Res inhibits the MSU-induced activation of NLRP3 inflammasomes by reducing the levels of IL-1β, IL-18, and Caspase-1 and the pyroptosis of macrophages. In addition, Res raises the level of mitochondrial membrane potential, inhibits the expression of P62 and Pink1, enhances the expressions of LC3B-II, Parkin, and TOMM20, and promotes mitophagy, while mitophagy inhibitors reverse the inhibitory effect of Res on the activation of NLRP3 inflammasomes.ConclusionRes significantly improves GA, and the underlying mechanism might be inhibiting the activation of NLRP3 inflammasomes by triggering the Pink1/Parkin pathway to promote mitophagy.

MiR-192-5p suppresses M1 macrophage polarization via epiregulin (EREG) downregulation in gouty arthritis

Celastrol ameliorates Propionibacterium acnes/LPS-induced liver damage and MSU-induced gouty arthritis via inhibiting K63 deubiquitination of NLRP3

Gouty arthritis (GA) is an inflammatory arthritic disorder that is characterized by intense, acute inflammatory responses, such as synovitis and arthritis that occur due to articular deposition of monosodium urate (MSU) crystals. This study has compared the therapeutic potentials of either Berberine (BERB) or Paracetamol (Para) on MSU-induced inflammation in rat model of Gouty arthritis (GA). GA was induced by “intra-articular” injection of MSU suspension (20 mg/ml) inside the knee joint of the rat’s right limb. Circumference was measured at 48 h after MSU injection and 14 days post-treatment with BERB or Para. Gait assessment was conducted. Histopathological alterations of knee and paw (ankle) joint tissue were investigated. Serum levels of Malondialdehyde (MDA), monocyte chemotactic protein 1 (MCP-1), Vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE2) were estimated. Molecular analysis of Elastase, Cyclooxygenase-2 (COX-2), Matrix metalloproteinase-9 (MMP-9), and Myeloperoxidase (MPO) was evaluated. In addition, DNA fragmentation assay was performed. Our results revealed that deposition of MSU crystals in the articular joints provoked an inflammatory response, oxidative stress, and DNA fragmentation (apoptosis). However, the oral treatment of MSU-induced rats with either BERB (50 mg/kg/day) or Para (50 mg/kg/day) for 14 days mitigated MSU-stimulated inflammation and arthritis as represented by the behavioral, histopathological, biochemical, and molecular levels. Treatment of MSU-induced arthritic rats with BERB or Para attenuated oedema and alleviated histological signs of acute inflammation. In addition, treatment decreased chemokine levels and reduced MDA levels. These results indicated that BERB and Para exerted strong anti-inflammatory, anti-oxidative, and anti-apoptotic activities against GA.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-16622-0.

Acute gouty arthritis is a self-limiting inflammatory disease resulting from the deposition of monosodium urate (MSU) crystals. It has been shown that Gentiopicroside (GPS) possesses anti-inflammatory and analgesic functions. The aim of this study was to parse out whether GPS has an effect on acute gouty arthritis. We established an acute gouty arthritis model by the injection of MSU into the paw, and found that GPS relieves MSU-induced mechanical, thermal hyperalgesia, and paw swelling. Furthermore, GPS down-regulated the release of pro-inflammatory cytokines in paw tissues, including IL-1β, IL-6, IL-18, and TNF-α. The results of H&E staining and MPO activity measurement showed that GPS inhibits neutrophil infiltration. And the over-expressions of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and Caspase-1 induced by MSU were inhibited by treatment with GPS. These results revealed that GPS can treat acute gouty arthritis based on anti-inflammatory and analgesic properties in vivo, which might be ascribed to the inhibition on NLRP3 inflammasome. Furthermore, we performed in vitro study to confirm the results of in vivo study. Consistently, the results proved that GPS could inhibit the activation of NLRP3 inflammasome in RAW264.7 macrophages stimulated by LPS-MSU. In conclusion, this study provides an experimental basis for the application of GPS and expands the potential value of GPS in the therapy of acute gouty arthritis.

Gouty arthritis (GA) is an immune disease caused by the deposition of monosodium urate (MSU) crystals. As living standards improve and lifestyles change, GA exhibits a high incidence rate, low cure rate, and multiple complications. However, the pathophysiological mechanism of GA remains incompletely understood, underscoring the importance of identifying effective therapeutic targets. Neutrophil extracellular traps (NETs) are complex network structures composed of DNA, histones, and various granule proteins, possessing antimicrobial and pathogen clearance functions. Their formation process, termed NETosis, is a programmed cell death mode unique to neutrophils. In GA, MSU crystals can activate NETosis through multiple mechanisms. The resulting NETs can either form aggregates to degrade and package MSU crystals and inflammatory factors, alleviating GA, or promote GA inflammation and tissue damage by activating macrophages to release inflammatory factors. In recent years, NETs have garnered significant attention as potential therapeutic targets for GA. This article reviews the functions and structures of NETs and summarizes several key mechanisms involved in regulating MSU crystal-induced NETosis, while elucidating the specific roles of these NETs in GA. In addition, beyond neutrophils, other myeloid cells such as eosinophils, basophils, and macrophages can also release extracellular traps, and this review explores their potential roles and mechanisms in GA. Finally, this review summarizes some drugs with the potential to target NETs for GA treatment and outlines their limitations. These findings enhance the understanding of interactions between NETs and GA, aiming to propose innovative therapeutic strategies and new approaches for GA prevention and treatment.

Few studies have systematically and quantitatively addressed the impact of urate-lowering therapy on monosodium urate (MSU) deposits. This study was undertaken to analyze the effect of lifestyle measures and conventional urate-lowering therapy on MSU deposits in patients with gout. In this prospective study, subjects with gout according to the American College of Rheumatology/European League Against Rheumatism classification criteria and presence of MSU deposits seen on dual-energy computed tomography (DECT) scans received either lifestyle intervention or conventional urate-lowering therapy for a mean period of 18 months before a follow-up DECT scan. Detected MSU deposits were quantified by volumetric measurement and validated by semiquantitative scoring, and baseline and follow-up measurements were compared. Baseline and follow-up DECT scans were available for all 83 subjects. Six subjects discontinued treatment, and 77 subjects underwent a lifestyle intervention (n = 24) or were treated with allopurinol (n = 29), febuxostat (n = 22), or benzbromarone (n = 2) over the entire observation period. The mean serum uric acid (UA) level decreased from 7.2 to 5.8 mg/dl in the overall population. In patients who discontinued treatment, no change in MSU deposits or serum UA levels was observed. The burden of MSU deposits significantly decreased in patients undergoing lifestyle intervention (MSU volume P = 0.007; MSU score P = 0.001), and in patients treated with allopurinol (MSU volume and score P < 0.001) or febuxostat (MSU volume P < 0.001; MSU score P = 0.001). No significant decline in MSU deposits was noted in patients who discontinued treatment. These data show that lifestyle intervention and xanthine oxidase inhibitors significantly decrease the MSU deposit burden. Hence, conventional gout therapy not only lowers serum UA levels, but also reduces pathologic MSU deposits.

LncRNA transcriptomics elucidates the suppression of gouty arthritis-associated pyroptosis by Pulchinenoside B4 through NLRP3 inflammasome modulation.