Search Results (1,762)

Background/Objectives: Chronic inflammation sustained by cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) underlies many human diseases, while the cardiovascular liabilities of coxibs have renewed interest in plant-derived alternatives. This study characterised the volatile composition of Corymbia citriodora essential oil under two distillation regimes and identified constituents able to inhibit human COX-2 and iNOS. Methods: Oils obtained by steam distillation (SD) and microwave-assisted steam distillation (MSD) were profiled by GC–MS/MS. All identified constituents were screened with SASA Vina against human COX-2 (PDB: 5KIR, 3LN1), ovine COX-1 (4COX) and human iNOS (3E7G), with native-ligand re-docking validating each protocol (RMSD 0.39–0.84 Å). The lead compound underwent density functional theory (B3LYP/3-21G/CPCM), 100 ns all-atom molecular dynamics, MM/GBSA and MM/PBSA decomposition, and pkCSM ADMET prediction. Results: Sixty-three constituents were identified (99.85% SD; 99.97% MSD). MSD enriched oxygenated monoterpenes (93.23% versus 88.27%), citronellal rose from 38.24% to 48.41%. (Z,Z,Z)-1,5,9,9-Tetramethyl-1,4,7-cycloundecatriene ranked highest at COX-2 (−8.0 to −8.2 kcal/mol) and also bound COX-1 (−8.8 kcal/mol) and iNOS (−6.8 kcal/mol). DFT indicated high kinetic stability (ΔE = 6.12 eV; η = 3.06 eV) and purely non-covalent hydrophobic binding. The COX-2 complex remained stable over 100 ns (Cα RMSD 0.17 ± 0.02 nm), with MM/GBSA and MM/PBSA binding energies of −23.98 and −21.95 kcal/mol and Val523 as the principal hotspot. ADMET prediction returned 96.61% human intestinal absorption and no mutagenicity, hepatotoxicity or hERG I blockade. Conclusions: MSD offers a faster route to a citronellal-enriched oil, and C. citriodora hydrocarbon sesquiterpenes emerge as chemically stable, multi-target COX-2/iNOS scaffolds. Comparable binding at COX-1 indicates that isoform selectivity remains to be established; in vitro enzymatic and cell-based validation is therefore required. Full article

Medicinal plants in the Acanthaceae family have long been used in Thai traditional medicine. In this study, ethanolic extracts of four plant species, Andrographis paniculata, Thunbergia laurifolia, Acanthus ebracteatus, and Rhinacanthus nasutus, were prepared and their phytochemical and pharmacological properties were evaluated. Total phenolic and flavonoid content assays were used to investigate phytochemical content and phytochemical profiles were characterized with LC-MS, while antioxidant activities were assessed via colorimetric methods. The extracts were also tested for antibacterial activity against several skin pathogens, such as Pseudomonas aeruginosa, Cutibacterium acnes, Micrococcus luteus, Staphylococcus aureus, and methicillin-resistant S. aureus, using agar well diffusion and broth dilution methods. Cytotoxic effects on the RAW 264.7 macrophage cell were assessed using the MTT assay. The extracts were further evaluated for anti-inflammatory activity in an LPS-stimulated RAW 264.7 cell. Inflammatory gene expression was assessed by quantifying the mRNA levels of iNOS, COX-2, TNF-α, IL-1β, IL-6, and NF-κB genes using RT-qPCR. The results revealed that among the four species, T. laurifolia extract showed the highest phenolic and flavonoid levels, consistent with the greatest antioxidant activity. Moreover, LC-MS profiling annotated a range of secondary metabolites in the extracts. The inhibition zones were observed for all plant extracts when tested against the skin pathogenic bacteria except C. acnes, and A. paniculata did not inhibit P. aeruginosa, indicating the antibacterial activity of the extracts. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values differed across the extracts and bacterial strains. T. laurifolia exhibited the most potent activity against various bacterial pathogens, while A. paniculata was most effective against C. acnes at 0.98 mg/mL. In addition, all plant extracts reduced nitric oxide production and downregulated the expression of inflammatory genes. Among all plant species, A. paniculata showed the most potent activity with the highest NO inhibition of 65.68% at 60 µg/mL. Therefore, these findings support the antioxidant, antibacterial, and anti-inflammatory potential of A. paniculata, T. laurifolia, A. ebracteatus and R. nasutus, which are traditionally used in folk medicine. Full article

Cuproptosis is a novel form of metabolism-associated cell death. Cervical cancer (CC) exhibits elevated serum copper levels and mitochondrial metabolic reprogramming, making cuproptosis-related genes (CRGs) potentially critical for prognosis prediction and therapeutic targeting. However, studies on CRGs in CC remain limited. This study aimed to construct prognostic and cancer staging models for CC using machine learning (ML) algorithms. Gene expression profiles of patients with CC were obtained from the TCGA and GEO databases. Five ML algorithms were employed to identify significant factors, including random forest (RF), support vector machine (SVM), Gaussian mixture model (GMM), Bayesian, and StepCox. A prognostic model was subsequently constructed using LASSO–Cox regression based on the selected genes. Concurrently, a cancer staging model was built using ML algorithms incorporating three distinct gene categories. Finally, qRT-PCR and Western blotting were conducted to validate the expression of signature genes at both the tissue and cellular levels. Additionally, CTD-based screening and in vitro functional assays were performed to evaluate the effects of DDP on CC cells. Through integrated bioinformatics and ML approaches, a prognostic model comprising nine CRGs was successfully established (GMM = 0.72). The derived risk score served as an independent prognostic indicator for CC (p < 0.001, 95% CI: 3.681 [1.785–7.591]). Calibration curves confirmed that the nomogram accurately predicted overall survival (OS) at 1, 3, and 5 years. Additionally, a cancer staging model was effectively constructed using the GMM algorithm (AUC = 0.74). DDP dose-dependently inhibited CC proliferation/migration and down-regulated CRG expression. In this study, we developed two different models—a cuproptosis-related prognostic model and a cancer staging model—that highlight promising biomarkers for predicting patient prognosis and cancer progression in patients with CC. Full article

Topical non-steroidal anti-inflammatory drugs (NSAIDs) such as flurbiprofen and benzydamine may be used for the symptomatic relief of pharyngitis, triggered by infections. The onset and spectrum of anti-inflammatory activity of both drugs were compared in human tonsil (HTEpiC) and bronchial epithelial (BEAS-2B) cells stimulated with poly I:C against key inflammatory mediators. Cells were stimulated with poly I:C for 24 h and treated with flurbiprofen or benzydamine for 20 s, 2 min and 5 min. Production of prostaglandin E2 (PGE₂), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), interleukin-8 (IL-8), interleukin-18 (IL-18), monocyte chemotactic protein-3 (MCP-3) and C-X-C motif chemokine ligand 10 (CXCL10), as well as cyclooxygenase-2 (COX-2) protein expression, was evaluated. Flurbiprofen significantly (p < 0.05) reduced PGE₂ production and COX-2 expression in both cell types within 20 s of treatment and maintained these effects at 2 and 5 min. However, benzydamine produced delayed, inconsistent inhibition. Although both drugs reduced poly I:C induced IL-6, IL-1β, IL-8 and IL-18 production, the magnitude and onset were greater with flurbiprofen. Flurbiprofen also reduced MCP-3 and CXCL10 in both cell types, alongside significant inhibition of caspase-1 activity. Benzydamine showed limited or no effect and less inhibition of caspase-1. With rapid suppression of the COX-2/PGE₂ pathway, rapid onset and a broad inhibition spectrum, flurbiprofen more comprehensively modulates inflammatory processes in epithelial respiratory models. Full article

Background: Neuropathic pain (NP) is a debilitating chronic condition driven by maladaptive neuroimmune interactions in the spinal cord, with microglia playing a central pathological role. Electroacupuncture (EA) has shown analgesic effects in clinical and preclinical studies, but the microglia-centered mechanisms underlying these effects remain incompletely integrated. This review aims to provide a comprehensive mechanistic synthesis of how EA modulates microglia-associated neuroinflammatory pathways in neuropathic pain. Methods: This systematic search-narrative review used systematic search and screening procedures to identify English-language animal studies published between 2015 and 2025 in PubMed, CINAHL, Web of Science, and Cochrane Library. Twenty-six animal studies investigating EA effects on microglia-associated signaling pathways in neuropathic pain models met the inclusion criteria. Because of substantial heterogeneity in neuropathic pain models, EA parameters, molecular endpoints, and behavioral outcomes, findings were synthesized narratively, and no meta-analysis was performed. Results: The reviewed evidence revealed four convergent mechanistic categories through which EA modulates microglial activity: (1) attenuation of purinergic microglial activation via downregulation of IRF8, P2X4R, P2X7R; (2) suppression of innate immune sensing and inflammasome pathways, including TLR4/MyD88/NF-κB and NLRP3 signaling; (3) inhibition of downstream inflammatory amplification through p38 MAPK, PI3K/AKT, and COX-2 pathways; and (4) promotion of pro-resolution mechanisms involving IL-10/β-endorphin, PD-L1, GRK2/TREM2/DAP12, α7nAChR, GLP-1R, and GABAergic signaling. Conclusions: The available preclinical evidence suggests that EA modulates multiple microglia-associated pathways, attenuating inflammatory signaling while enhancing selected pro-resolution mechanisms. These findings provide a mechanistic framework for understanding EA-induced analgesia in neuropathic pain and highlight microglial signaling networks as important targets for future experimental and translational investigation. Full article

Background/Objectives: Propolis is a resinous natural product rich in phenolic acids and flavonoids, recognized in ethnopharmacology for its antioxidant and anti-inflammatory properties. This study aimed to identify the most bioactive Saudi propolis extract using a bioassay-guided strategy and investigate its chemical profile and mechanistic anti-inflammatory potential. Methods: Four propolis extracts (P1–P4) collected from different regions of Saudi Arabia were evaluated for their antioxidant (DPPH and ABTS) and anti-inflammatory (COX-1 and COX-2) activities. The most active extract was profiled using liquid chromatography–mass spectrometry (LC–MS), followed by molecular docking and molecular dynamics simulations. Results: Among all samples, P3 demonstrated the strongest antioxidant activity, with IC₅₀ values of 25.84 ± 0.96 µg/mL (DPPH) and 32.30 ± 1.20 µg/mL (ABTS), comparable to ascorbic acid (27.45 ± 1.42 and 21.22 ± 0.79, respectively). P3 also exhibited potent and selective COX-2 inhibition with an IC₅₀ of 6.19 ± 0.21 µg/mL (relative to celecoxib, IC₅₀ 0.681 ± 0.02 as positive control). LC–MS analysis identified 26 secondary metabolites. Computational studies ranked kaempferol as forming the most conformationally stable COX-2 complex among the ligands examined, including the reference inhibitor, on the basis of molecular dynamics descriptors of pose persistence and conformational confinement. Conclusions: Saudi propolis P3 is a potent source of bioactive compounds with strong antioxidant and selective COX-2 inhibitory activity. These findings highlight its anti-inflammatory potential and suggest its value as a natural lead for developing safer therapeutics targeting inflammation-related chronic diseases. Full article

Cancer metastasis, characterized by the dissemination of malignant cells from the primary tumor to distant organs, remains the leading cause of cancer-related mortality in solid tumors. In colorectal cancer (CRC), increasing attention has been directed toward therapeutic strategies aimed at suppressing cancer cell migration and invasion rather than solely reducing tumor mass, giving rise to the concept of migrastatic therapies. In the present study, green-synthesized silver nanoparticles (AgNPs), previously obtained using aqueous extracts of Filipendula ulmaria (L.) Maxim. and Salvia verticillata L., were evaluated for their antimigratory and anti-inflammatory potential in human colorectal carcinoma HCT-116 cells. Treatment with AgNPs induced considerable perturbations in cellular redox homeostasis, as evidenced by increased intracellular reactive oxygen species (ROS), lipid peroxidation (LPO), glutathione (GSH), and nitric oxide (NO) levels. These redox alterations were accompanied by a significant inhibition of cancer cell migration, together with reduced expression of matrix metalloproteinases MMP-2 and MMP-9, key mediators of extracellular matrix remodeling associated with tumor progression. AgNP exposure was associated with activation of the cytoprotective transcription factor Nrf-2 and suppression of the pro-inflammatory NF-κB/COX-2 signaling axis, indicating coordinated modulation of redox-sensitive pathways linked to tumor cell motility and inflammatory responses. Collectively, these findings demonstrate that green-synthesized AgNPs derived from F. ulmaria and S. verticillata exert multi-level regulatory effects on redox balance, inflammatory signaling, and migration-associated molecular markers in colorectal cancer cells. This study supports their potential as promising migrastatic nanocarriers for further investigation in colorectal cancer research. Full article

Kansui Radix, the root of Euphorbia kansui, was first described in Shen Nong Ben Cao Jing as a traditional Chinese medicine, known for its effects of expelling water, reducing edema, and dissipating masses. It is traditionally indicated for conditions such as “watery accumulation” and “abdominal masses (zheng-jia)”, which share certain similarities with the clinical manifestations of renal cell carcinoma (RCC), including renal masses, edema, and body cavity effusion. Despite the recognized antitumor effects of Kansui Radix, the pharmacological basis and specific molecular mechanisms underlying its inhibition of RCC progression remain unclear. The goal of this study was therefore to evaluate the antitumor efficacy of Kansui-DCM in RCC and to explore its potential mechanism. To this end, the chemical composition of the dichloromethane fraction of Kansui Radix (Kansui-DCM) was characterized by UPLC-MS. The antiproliferative effects of Kansui-DCM on 786-O and RENCA cells were evaluated using the CCK-8 assay. Apoptotic morphology, apoptosis rate, cell migration and invasion abilities were assessed. An RCC mouse model was established, and tumor growth and histopathological staining were evaluated after drug administration. Immunohistochemistry, transcriptomic analysis, WGCNA (weighted gene co-expression network analysis), network pharmacology, and immunofluorescence were employed to investigate the molecular pathway. Protein and gene expression were analyzed by Western blot and qRT-PCR, respectively. Finally, the interactions between the active components and key targets were substantiated through molecular docking and molecular dynamics simulations. A total of 1397 compounds were detected in Kansui-DCM by UPLC-MS. In vitro experiments demonstrated that Kansui-DCM inhibited the proliferation of 786-O and RENCA cells in a dose-dependent manner, induced apoptosis, and suppressed cell invasion and migration in RENCA cells. Treatment with Kansui-DCM markedly suppressed tumor growth in vivo, as reflected by a reduction in tumor volume. Immunohistochemical analysis indicated that the expression levels of CD31, COX-2, and Ki67 were markedly decreased, while the expression level of CD8 was significantly increased. Integrated analysis using WGCNA and network pharmacology predicted that Kansui-DCM may exert its effects through the regulation of the HIF/VEGF signaling pathway, which was further validated by immunofluorescence, Western blot, and qRT-PCR assays. Molecular docking and molecular dynamics simulations demonstrated stable interactions between multiple active components of Kansui-DCM and key targets such as VEGFR2 and HIF-2α. In conclusion, these findings suggested that Kansui-DCM exerts anti-RCC effects associated with regulation of the HIF/VEGF pathway. Full article

Despite the well-established bioactivity of Salvia verticillata L. aerial parts, their roots represent an unexplored plant matrix. In this study, root extracts obtained by ethnopharmacological (EE), maceration (ME), and ultrasound-assisted (UE) extraction were examined. Ultrasound-assisted extraction was optimized using response surface methodology (RSM, CCD) to maximize total phenolic content (TPC) and rosmarinic acid (RA), and the optimized extract was compared with EE and ME. All extracts exhibited high levels of total phenolics, flavonoids, and phenolic acids, while RA was the dominant compound according to HPLC analysis (96.67–137.47 mg g⁻¹ d.e.). UE yielded the highest TPC and exhibited the strongest antioxidant activity in most of the applied assays. All extracts exhibited concentration-dependent tyrosinase inhibitory activity, with UE and EE showing the strongest effects. Moderate antibacterial activity, particularly against Gram-positive strains, and limited antifungal effects were observed. Strong COX-1 inhibition (>70% at 50 μg/mL) confirmed the anti-inflammatory potential of the extracts, whereas slight COX-2 inhibition was observed. UE exhibited moderate cytotoxic activity against A431, SVT2, and HaCaT cells. These findings identify S. verticillata roots as a promising source of rosmarinic acid-rich extracts and point out the importance of the extraction procedure to tailor the biological activity of the extract. Full article

Metastasis-associated protein 1 (MTA1), an oncogenic transcriptional regulator, is overexpressed in canine urothelial carcinoma (UC) and is associated with aggressive clinicopathological features. However, its functional role and molecular mechanisms in canine UC remain poorly understood. Here, we investigated the contribution of MTA1 to epithelial-to-mesenchymal transition (EMT) and its interaction with BRAF signaling. MTA1 silencing in two canine UC cell lines significantly inhibited cell proliferation, cell survival, migration, and xenograft tumor growth. Mechanistically, MTA1 knockdown reduced the expression of MTA2, MTA3, and COX2, while producing unexpected changes in key EMT regulators, including Snail, Slug, and Cyclin D1, suggesting the activation of compensatory signaling pathways. MTA1 silencing also decreased mutant BRAF expression in AxA cells while increasing wild-type BRAF expression in SH cells, indicating context-dependent regulation of BRAF signaling. In AxA cells, reduced AKT phosphorylation following MTA1 knockdown further supports functional crosstalk between the BRAF and MTA1/AKT signaling pathways. Collectively, these findings identify MTA1 as a critical regulator of canine UC progression and reveal complex signaling interactions that support its potential as a therapeutic target for canine UC. Full article

Purpose: This study investigated the molecular mechanisms underlying blue light-induced corneal epithelial toxicity. Methods: C57BL/6J mice were exposed to 460 nm blue light for 1, 2, or 4 weeks, whereas human corneal epithelial (HCE) cells were exposed for 15 or 30 min. RNA-sequencing with bioinformatic analysis identified p53 signaling and ferroptosis as key pathways. p53 knockdown using siRNA and pharmacological inhibition with pifithrin-α (PFT-α) were employed to validate the mechanism in vitro and in vivo. Results: Blue light exposure caused time-dependent corneal epithelial disruption, reduced tear film stability, increased inflammatory cell infiltration, downregulated K12 expression, and upregulated K10 expression. Blue light induced cell death and G1-phase cell-cycle arrest in HCE cells. Ferroptosis hallmarks included intracellular ferrous iron (Fe²⁺) accumulation, reactive oxygen species (ROS) generation, decreased SLC7A11 and GPX4 expression, and increased COX2 expression. RNA sequencing revealed p53 pathway activation as a master regulator of ferroptosis. p53 knockdown reversed blue light-induced SLC7A11/GPX4 suppression and COX2 upregulation. Topical PFT-α administration attenuated corneal epithelial damage, restored K12 expression, suppressed K10 expression, and normalized ferroptosis markers in vivo. Conclusions: Blue light pollution triggers corneal epithelial ferroptosis through p53-mediated SLC7A11/GPX4 axis suppression. Pharmacological inhibition of p53 represents a promising therapeutic strategy for blue light-associated dry eye. Full article

A light-promoted C–H/C–H coupling of imidazo[1,2-a]pyridines with 5-(hetero)aryl-1,2,5-oxadiazolo[3,4-b]pyrazines was developed using a heterogeneous oxidative photocatalytic system based on molecular oxygen, nanosized TiO₂, and light irradiation. The method provides direct access to C3-heteroarylated imidazo[1,2-a]pyridines under metal-free conditions and expands the synthetic utility of electron-deficient oxadiazolopyrazine partners in the construction of biheteroaryl scaffolds. The synthesized compounds were evaluated computationally using a fully connected convolutional correlation neural network based on multiple-docking energy spectra, which prioritized the series as potential COX-1 and COX-2 ligands. To test this prioritization experimentally, all 18 compounds were screened in fluorometric COX-1 and COX-2 inhibitor assays at 1 µM. Compound 3f emerged as a strong preliminary COX-1 hit at 1 µM (86.64 ± 5.18% inhibition), whereas 3h and 3l showed weaker COX-1 inhibition. No compound showed high or moderate COX-2 inhibition at the screening concentration; only weak COX-2 inhibitory signals were observed for several derivatives. Thus, the combined synthetic, computational, and enzymatic data identify compound 3f as the main COX-1-skewed hit in this series and provide a basis for further dose–response, selectivity, and cell-based anti-inflammatory studies. It should also be noted that the COX-1 inhibition assay used ovine COX-1, whereas the computational models were built on human COX-1 and COX-2 structures; this species difference is an additional reason to treat the in silico–experimental comparison as approximate. Full article

The effect of Corosolic acid (CA) on vascular tone and the possible mecha-nisms involved remain unclear. The SPF-grade male Sprague-Dawley rats (Animal Ethics Approval ID: USM/IACUC/2025/(155)(1406)) were used. The vasorelaxant effects of CA were evaluated in endothelium-intact and endothelium-denuded rings precontracted with phenylephrine (PE), and in endothelium-intact rings precontracted with KCl. Possible mechanisms were examined using L-NAME, ODQ, methylene blue, indomethacin, atropine, propranolol, and potassium channel blockers (glibenclamide, TEA, BaCl₂, and 4-AP). The effects of CA on voltage-operated calcium channels (VOCCs) and IP₃ receptor (IP₃R)-mediated sarcoplasmic reticulum calcium release were also assessed. CA concentration-dependently relaxed endothelium-intact aortic rings precontracted with PE (RMAX = 90.08 ± 7.33%; pD₂ = 4.21 ± 0.08). The relaxation response was markedly reduced after endothelial removal and in KCl-precontracted rings. EDRF pathway inhibitors (L-NAME, ODQ, methylene blue, and indomethacin) and GPCR-related antagonists (atropine and propranolol) attenuated CA-induced relaxation. Among potassium channel blockers, glibenclamide and TEA showed stronger inhibitory effects. CA did not significantly inhibit VOCC-mediated CaCl₂-induced contraction but partially reduced PE-induced contraction under calcium-free conditions. The mechanisms for CA treating hypertension may involve NO/cGMP signalling, COX-related prostanoid pathways, GPCR-related mechanisms, potassium channel modulation, and partial inhibition of IP₃R-mediated calcium release. Full article

Solanum elaeagnifolium has been utilized for its analgesic, anti-inflammatory, and antioxidant properties to treat a range of conditions, including pain and inflammation. It possesses antibacterial, insecticidal, and molluscicidal properties as well. To investigate the pharmacological potential of the S. elaeagnifolium extract, in vitro, in vivo, and in silico studies were used. Albumin denaturation, heat-induced anti-haemolytic action, and lipooxygenase inhibition were the three techniques used to test anti-inflammatory effectiveness. The phenolic chemicals utilized were identified through the use of high-performance liquid chromatography (HPLC). The effectiveness of the extract in lowering problems connected to diabetes was further evaluated by evaluating fructosamines, carbonyl groups, and β-amyloid formations in albumin glycation. Regarding in vivo studies, the Writhing test and the tail flick test were the two techniques used to evaluate analgesic activity. For docking analysis, we used the following identifiers: cyclooxygenase (PDB ID: 6COX), lipooxygenase (PDB ID: 3V99) and VC1 domain of the receptor for advanced glycation products (PDB ID: 7LMW). The most prevalent phenolic chemicals, according to HPLC analysis, were 3,4-dihydroxybenzoic acid (4.78%), caffeic acid (1.28%), gallic acid (8.18%), ursolic acid (2.6%), syringic acid (1.78%), quercetin (24.09%), catechin (6.67%), and p-coumaric acid (20.49%). Significant suppression of albumin glycation and fructosamine production was demonstrated by the extract, indicating that it may help lessen difficulties associated with diabetes. Furthermore, the extract demonstrated a strong anti-inflammatory impact, with an IC₅₀ of 146 ± 1.17 μg/mL for lipooxygenase inhibition, 87.64 ± 5.35 μg/mL for anti-haemolytic action, and 86.94 ± 1.63 μg/mL for albumin denaturation inhibition. A similar analgesic effect to those of analgesic medications was also demonstrated by SEFE extract. Reinforcing the relevance of the observed effects, the in silico study of the tested activities validated these findings. These findings indicate significant pharmacological promise in the management of diabetes consequences, including inflammation and protein glycation, as well as an analgesic. Full article

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) remain the cornerstone of pharmacological treatment for osteoarthritis (OA) and are recommended by international guidelines for the management of symptomatic pain. Despite their well-established efficacy, substantial interindividual variability exists in treatment response, with some patients experiencing meaningful pain relief while others derive little clinical benefit despite appropriate drug selection and dosing. This variability reflects, at least in part, the biological heterogeneity of OA pain. Objective: To review the mechanisms underlying variability in NSAID responsiveness in OA and to propose a practical framework for personalized NSAID prescribing based on pain phenotype, individual safety profile, and treatment timing. Methods: A narrative review of the contemporary scientific literature was conducted using major biomedical databases to summarize the current evidence on phenotype-guided NSAID therapy in OA. Particular attention was given to the emerging concepts of nociceptive, nociplastic, and neuropathic-like pain phenotypes and their implications for personalized anti-inflammatory therapy. Results: Current evidence indicates that OA pain is a heterogeneous and dynamic condition in which inflammatory nociceptive, nociplastic, and neuropathic-like mechanisms coexist to varying degrees. NSAIDs primarily target inflammatory nociceptive pain by inhibiting cyclooxygenase (COX)-mediated prostaglandin synthesis and reducing peripheral sensitization. Consequently, patients with predominantly inflammatory nociceptive pain are the most likely to benefit from NSAID therapy, whereas those with predominant nociplastic or neuropathic-like pain mechanisms may require alternative or multimodal treatment strategies. Beyond pain phenotype, optimal NSAID selection should integrate cardiovascular, gastrointestinal, and renal risk assessment, recognizing the important pharmacological and safety differences among individual agents. Treatment timing is also clinically relevant, as anti-inflammatory therapy appears most effective when initiated during periods of active inflammatory nociceptive pain. Based on the available evidence, we propose a conceptual clinical decision framework integrating patient selection, NSAID choice, and treatment timing. Conclusions: Personalized NSAID prescribing should move beyond a diagnosis-based approach toward a mechanism-based strategy that integrates pain phenotyping, individualized safety assessment, and appropriate treatment timing. The proposed framework is built upon three complementary principles, identifying the right patient, selecting the right treatment, and initiating therapy at the right time. It provides a practical foundation for implementing precision medicine in the pharmacological management of OA. Full article