Glucagon-like peptide-1 (GLP-1) is a 30–amino acid incretin hormone derived from post-translational processing of proglucagon in intestinal L-cells. Secreted in response to nutrient ingestion, endogenous GLP-1 has a circulating half-life of only 1-2 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-4). Despite its brevity, GLP-1 exerts pleiotropic physiological effects through the widely distributed GLP-1 receptor (GLP-1R), a class B G protein-coupled receptor (GPCR) expressed in the pancreas, heart, kidney, liver, lung, central nervous system, and immune cells[1, 2]. The primary physiological actions of GLP-1 include glucose-dependent stimulation of insulin secretion, suppression of glucagon release, delayed gastric emptying, and central appetite suppression. However, this classical incretin framework represents only a fraction of GLP-1R biology; receptor activation initiates a complex intracellular signalling cascade involving cyclic AMP (cAMP), protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) pathways, each with downstream effects on inflammation, oxidative stress, and cell survival[1, 2]. GLP-1RAs are engineered peptides designed to resist DPP-4 degradation while retaining or enhancing GLP-1R agonism. The class spans a clinical spectrum from short-acting, meal-time agents (exenatide twice daily, lixisenatide) to long-acting weekly formulations (semaglutide, dulaglutide, albiglutide) and the first oral GLP-1RA (oral semaglutide). More recently, tirzepatide, a dual GIP/GLP-1 receptor agonist, has demonstrated superior glycaemic and weight-loss outcomes, with emerging evidence of additional anti-inflammatory effects mediated by GIP receptor co-activation[3]. Approved indications have expanded from T2DM to obesity (semaglutide 2.4 mg, liraglutide 3.0 mg) and, in select agents, primary cardiovascular risk reduction. The cardiovascular outcome trials (CVOTs) LEADER, SUSTAIN-6, HARMONY OUTCOMES, and REWIND documented significant reductions in major adverse cardiovascular events (MACE) of 13–26%, with residual benefit persisting after adjustment for glycaemic and weight changes, strongly implicating GLP-1R-specific mechanisms, including anti-inflammatory effects[4]. This narrative review was conducted using literature retrieved from PubMed, Scopus, Web of Science, and Google Scholar databases. Keywords included "GLP-1 receptor agonists," "inflammation," "oxidative stress,” "NF-κB," “Nrf2," and "NLRP3 inflammasome." Articles published in English between 2005 and 2026 were considered. Priority was given to peer-reviewed mechanistic studies, randomized clinical trials, meta-analyses, and translational studies relevant to the inflammatory and antioxidant effects of GLP-1 receptor agonists.

Chronic low-grade inflammation and sustained oxidative stress are now recognised as central pathophysiological drivers in T2DM, obesity, non-alcoholic fatty liver disease (NAFLD/MASH), atherosclerosis, and diabetic nephropathy. Nuclear factor-κB (NF-κB), the master transcriptional regulator of inflammation, and the NLRP3 inflammasome, the principal innate immune complex mediating IL-1β maturation, are constitutively hyperactivated in these conditions. Simultaneously, the Nrf2 antioxidant defense system, which governs expression of heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), is functionally suppressed[5, 6]. These two axes are not independent: reactive oxygen species (ROS) activate NF-κB and prime the NLRP3 inflammasome. At the same time, inflammatory signalling upregulates NADPH oxidases (NOX2/NOX4) and iNOS, thereby generating additional ROS and creating a self-amplifying pathological feedback loop. GLP-1RAs, by virtue of their engagement with a receptor coupled to both cAMP/PKA and PI3K/Akt, are uniquely positioned to interrupt this loop at multiple nodes simultaneously[6-8]. This review provides a comprehensive mechanistic analysis of the anti-inflammatory and antioxidant properties of GLP-1RAs, organized around: 

We also address the bidirectional crosstalk between oxidative stress and inflammation, the emerging pharmacology of dual- and triple-receptor agonists, and priority research gaps.

The GLP-1R is a 463-amino acid class B GPCR characterized by a large extracellular N-terminal domain that forms the primary peptide-binding site. Upon GLP-1 or GLP-1RA engagement, the receptor undergoes conformational changes that promote Gαs coupling and subsequent adenylyl cyclase activation. GLP-1R expression is heterogeneous: highest in pancreatic beta cells and alpha cells, with significant expression in cardiac myocytes, vascular endothelium, renal tubular epithelium, adipocytes, macrophages, microglia, and enteric neurons. This broad distribution underpins the pleiotropic pharmacological profile of GLP-1RAs and accounts for their organ-specific anti-inflammatory effects[9-11].

The predominant signalling pathway downstream of GLP-1R activation is Gαs-mediated stimulation of adenylyl cyclase, which converts ATP to intracellular cAMP. Elevated cAMP activates two primary effectors: protein kinase A (PKA) and exchange protein activated by cAMP (Epac). PKA phosphorylates a broad spectrum of substrates with anti-inflammatory and antioxidant consequences: IKKβ (disrupting NF-κB activation), NLRP3 (preventing inflammasome assembly), CREB (inducing anti-inflammatory gene expression), and Nrf2 co-activators. Epac signalling contributes to calcium mobilization, mitochondrial quality control, and M2 macrophage polarisation[12, 13].

Beyond Gαs, GLP-1R activates PI3K/Akt signalling, which phosphorylates and activates Nrf2 (at Ser40 via Akt-downstream kinases) while inhibiting GSK-3β, a kinase that otherwise exports Nrf2 from the nucleus. PI3K/Akt also activates mTORC1 in a context-dependent manner and suppresses FoxO transcription factors, reducing pro-apoptotic and pro-inflammatory gene expression. ERK1/2 (MAPK) activation downstream of GLP-1R promotes cell survival and has been linked to macrophage polarisation. β-Arrestin-mediated receptor internalization, independent of G-protein Signalling, initiates a distinct wave of Signalling from endosomes, providing sustained anti-inflammatory effects beyond the initial cAMP burst[14-17].

GLP-1RA signalling intersects substantially with the insulin receptor/IRS-1/PI3K axis, leptin receptor JAK-STAT signalling, and adiponectin signalling. GLP-1RAs enhance insulin sensitivity, in part, through anti-inflammatory mechanisms. TNF-α and IL-6 are canonical inducers of IRS-1 serine phosphorylation and insulin resistance. By suppressing these cytokines, GLP-1RAs reduce an important driver of metabolic inflammation. Simultaneously, GLP-1RAs increase circulating adiponectin, which itself activates AMPK and exerts anti-inflammatory and antioxidant effects, creating a reinforcing feed-forward loop[18, 19].

1) Anti-Inflammatory Mechanism

NF-κB Signalling Inhibition:

NF-κB is the master transcriptional regulator of inflammation, governing expression of over 150 target genes, including TNF-α, IL-1β, IL-6, IL-8, COX-2, iNOS, MCP-1, VCAM-1, ICAM-1, and E-selectin. In the canonical pathway, pro-inflammatory stimuli (LPS, TNF-α, free fatty acids, hyperglycemia, AGEs) activate the IκB kinase (IKK) complex, which phosphorylates inhibitory IκBα, leading to its ubiquitination and proteasomal degradation. Released NF-κB p65/p50 dimers translocate to the nucleus and drive inflammatory gene transcription[12, 15].

GLP-1RAs interrupt this pathway at multiple steps. PKA directly phosphorylates IKKβ at Ser177 and Ser181, suppressing kinase activity and stabilizing IκBα. Additionally, cAMP promotes IκBα resynthesis through CREB-dependent transcription, providing dual protection. PKA-activated CREB can also compete with p65 for coactivator binding to CBP/p300, further suppressing NF-κB transcriptional output. These mechanisms collectively account for the 15–40% reductions in circulating TNF-α, IL-6, IL-1β, and CRP documented in clinical trials of liraglutide, exenatide, and semaglutide[12, 20].

NLRP3 Inflammasome Suppression:

The NLRP3 inflammasome is a multiprotein complex (NLRP3, ASC, pro-caspase-1) critical for innate immune responses in cardiometabolic disease. Activated by diverse danger signals, including cholesterol crystals, fatty acids, uric acid, ATP, and ROS, NLRP3 drives caspase-1-mediated cleavage and secretion of IL-1β and IL-18, which are potent inducers of vascular and metabolic inflammation. GLP-1RAs suppress NLRP3 activation via PKA-mediated phosphorylation of NLRP3 at Ser295, thereby preventing its oligomerization and recruitment of ASCs. This direct phosphorylation is cAMP-dependent and has been demonstrated in macrophages, adipocytes, and cardiomyocytes exposed to liraglutide and semaglutide, with downstream reductions in caspase-1 activity and mature IL-1β secretion of 30–60% in preclinical models[21, 22]. 

Macrophage Polarization M1 to M2 Phenotype Shift:

Macrophage polarisation is a critical determinant of tissue inflammation in obesity, atherosclerosis, and NAFLD. Pro-inflammatory M1 macrophages (activated by LPS and IFN-γ) produce TNF-α, IL-1β, IL-12, and reactive nitrogen species, while anti-inflammatory M2 macrophages (activated by IL-4, IL-13) secrete IL-10, TGF-β, and arginase-1. GLP-1RAs promote M1-to-M2 polarisation through cAMP/Epac-mediated PPARγ activation and AMPK phosphorylation, effects corroborated by transcriptomic studies in adipose tissue macrophages from liraglutide-treated obese mice, showing enrichment of M2-associated gene signatures and a reduction in M1 markers[23-25].

Endothelial Anti-Inflammatory Effects:

Endothelial dysfunction, characterized by upregulation of adhesion molecules (VCAM-1, ICAM-1, E-selectin) and reduced nitric oxide (NO) bioavailability, is an early and critical step in atherogenesis. GLP-1RAs directly activate endothelial GLP-1Rs, increasing cAMP, activating eNOS through PKA and Akt phosphorylation (Ser1177), and stimulating NO production. Simultaneously, NF-κB inhibition reduces adhesion molecule expression, diminishing monocyte-endothelial interactions. In human aortic endothelial cells exposed to high glucose, liraglutide treatment reduced VCAM-1 and ICAM-1 expression by 40–55%, accompanied by IκBα stabilization and preserved eNOS coupling[26, 27].

Gut Microbiome Modulation:

Intestinal dysbiosis, characterized by reduced microbial diversity, overgrowth of gram-negative LPS-producing bacteria, and impaired gut barrier integrity, drives systemic endotoxemia and low-grade inflammation in obesity and T2DM. GLP-1RAs, by slowing gastric emptying and exerting direct effects on intestinal L-cells and enteric neurons, alter the composition of the gut microbiome. Clinical studies of semaglutide and liraglutide report increased abundances of Akkermansia muciniphila and Faecalibacterium prausnitzii, organisms associated with mucosal integrity and anti-inflammatory short-chain fatty acid (SCFA) production, alongside reduced circulating LPS and LPS-binding protein[28].

Central Nervous System Anti-Inflammatory Effects:

GLP-1Rs are expressed on microglia, astrocytes, hypothalamic neurons, and dopaminergic neurons of the substantia nigra. In models of neuroinflammation relevant to obesity and neurodegeneration, GLP-1RAs suppress microglial NF-κB activation, reduce TNF-α and IL-6 secretion in the CNS, and promote microglial M2 polarization. In Parkinson's disease models, liraglutide reduced dopaminergic neuron loss associated with LPS-induced neuroinflammation. Semaglutide has shown reductions in amyloid-β-induced ROS and tau hyperphosphorylation in Alzheimer's disease animal models, supporting emerging clinical trials in neurodegeneration[26, 29].

2) Antioxidant Mechanisms Nrf2/Keap1 Antioxidant Pathway Activation

The Nrf2 (nuclear factor erythroid 2-related factor 2) transcription factor is the central regulator of the cellular antioxidant defense system.  Under basal conditions, Nrf2 is retained in the cytoplasm by its repressor Keap1 (Kelch-like ECH-associated protein 1), which promotes Nrf2 ubiquitination and proteasomal degradation with a half-life of approximately 20 minutes. Oxidative modification of Keap1 cysteine residues (Cys151, Cys273, Cys288) dissociates the complex, allowing Nrf2 to accumulate in the nucleus and bind to antioxidant response elements (AREs). GLP-1RAs activate Nrf2 through both PKA-dependent (Nrf2 Ser40 phosphorylation) and PI3K/Akt-dependent (GSK-3β inhibition, preventing Nrf2 nuclear export) mechanisms. This dual activation stabilizes nuclear Nrf2 and drives sustained expression of: HO-1 (heme oxygenase-1), NQO1 (NAD(P)H quinone oxidoreductase-1), SOD1/2 (superoxide dismutases), catalase, glutathione peroxidase (GPx), glutamate-cysteine ligase (GCL, rate-limiting for GSH synthesis), thioredoxin, and ferritin. Clinical studies document 20–45% increases in total antioxidant capacity and significant elevations in SOD and catalase activities in T2DM patients treated with liraglutide[15, 30, 31].

NADPH Oxidase Inhibition:

NADPH oxidases (NOX enzymes), particularly NOX2 and NOX4, are the primary enzymatic sources of superoxide anion in cardiovascular and inflammatory cells. NOX2 is expressed predominantly in macrophages, neutrophils, and vascular smooth muscle cells, where it forms a multiprotein 

complex (gp91phox, p22phox, p47phox, p67phox, p40phox, and Rac1). GLP-1RAs suppress NOX2 assembly through PKA-mediated phosphorylation of p47phox, preventing its membrane translocation and Rac1 co-activation. NOX4, constitutively active in the endothelium and kidney, is transcriptionally downregulated by Nrf2 activation and by GLP-1RA-induced reduction in ER stress, which is a major inducer of NOX4 expression[32, 33].

Note: HO-1 = heme oxygenase-1; NQO1 = NAD(P)H: quinone oxidoreductase 1; SOD = superoxide dismutase; GPx = glutathione peroxidase; GSH = glutathione; MDA = malondialdehyde; 4-HNE = 4-hydroxynonenal; AGE = advanced glycation end-product; RAGE = receptor for AGE; ER = endoplasmic reticulum; ROS = reactive oxygen species; UPR = unfolded protein response.

Mitochondrial Control and Biogenesis:

Dysfunctional mitochondria are a major source of intracellular ROS via electron leakage from Complexes I and III of the electron transport chain. GLP-1RAs promote mitochondrial health through multiple convergent mechanisms. PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), the master regulator of mitochondrial biogenesis, is upregulated by cAMP/CREB and AMPK signalling downstream of GLP-1R activation. AMPK activation also promotes mitophagy through ULK1 phosphorylation and induction of the PINK1-Parkin pathway, selectively eliminating depolarized, ROS-generating mitochondria. In diabetic cardiomyopathy models, liraglutide treatment preserved mitochondrial membrane potential, increased mtDNA copy number by 35%, and reduced 4-hydroxynonenal (4-HNE) protein adducts, a marker of lipid peroxidation-driven mitochondrial damage[34, 35].

Lipid Peroxidation and AGE Reduction:

Lipid peroxidation, the oxidative degradation of polyunsaturated fatty acids by ROS, generates reactive aldehydes (MDA, 4-HNE, acrolein) that form protein adducts, disrupt membrane function, and amplify inflammation. GLP-1RAs reduce lipid peroxidation markers (MDA, isoprostanes) by 25–45% in clinical studies, 

attributable to direct ROS scavenging via Nrf2-induced antioxidant pathways, reduced substrate availability through weight loss, improved lipid profiles, and decreased lipoxygenase and cyclooxygenase activity via NF-κB suppression. Advanced glycation end-products (AGEs), formed by non-enzymatic glycation of proteins and lipids in hyperglycaemic conditions, activate the RAGE receptor to generate ROS and induce NF-κB. GLP-1RAs reduce AGE formation through glycaemic control and independently downregulate RAGE expression in endothelial and renal cells[36-39].

1) Cardiovascular System

The cardiovascular anti-inflammatory effects of GLP-1RAs are among the best-characterized, supported by both mechanistic studies and large CVOTs. In the vascular wall, GLP-1RAs reduce macrophage foam cell formation by suppressing cholesterol crystal-induced NLRP3 activation and promoting ABCA1-mediated cholesterol efflux. They attenuate VCAM-1 and ICAM-1-mediated monocyte recruitment, reducing plaque macrophage density. In the myocardium, GLP-1RAs provide ischemia-reperfusion protection through cAMP-mediated activation of the RISK (Reperfusion Injury Salvage Kinase) pathway and opening of mitochondrial KATP channels, effects demonstrated in both rodent and porcine cardiac models. The LEADER trial (liraglutide, n=9,340) and SUSTAIN-6 (semaglutide, n=3,297) each documented significant reductions in MACE, with post hoc analyses indicating associations between reductions in CRP and reductions in CV event risk, suggesting that anti-inflammatory mechanisms contribute incrementally to cardioprotection beyond glycaemic improvement[40].

2) Liver NAFLD and Non-Alcoholic Steatohepatitis

GLP-1Rs are expressed on hepatic stellate cells and, at low levels, on hepatocytes, with significant indirect hepatic effects mediated by reduced adipose tissue lipolysis and central appetite suppression. In NAFLD/NASH models, GLP-1RAs reduce hepatic steatosis by suppressing de novo lipogenesis (via SREBP-1c downregulation). At the same time, anti-inflammatory effects include reduced Kupffer cell TNF-α and MCP-1 secretion, hepatic NF-κB activity, and hepatic stellate cell activation (TGF-β, α-SMA). The LEAN trial (liraglutide, 72 weeks) demonstrated histological improvement in NASH in 39% vs 9% of placebo patients. The phase 3 semaglutide NASH trial (n=320) reported NASH resolution in 59% vs 17% in controls, with a reduction in liver inflammation score of 2.1 points vs 0.8 points. Mechanistically, hepatic oxidative stress markers (MDA, 8-OHdG) decreased significantly and correlated with upregulation of Nrf2 and HO-1 in paired liver biopsies[41, 42].

3) Kidney Diabetic Nephropathy

Diabetic nephropathy (DKD) is driven by a combination of glomerular hemodynamic stress, inflammation, and oxidative injury to tubular and mesangial cells. GLP-1Rs are expressed on renal proximal tubular cells and medullary collecting ducts, enabling direct renal effects beyond systemic glycaemic improvement. GLP-1RAs reduce glomerular macrophage infiltration, mesangial NF-κB activity, and tubular ICAM-1 expression in DKD models. Oxidative stress biomarkers (8-OHdG and MDA in urine and renal tissue) are significantly reduced, accompanied by increased expression of catalase and SOD2. The REWIND trial (dulaglutide, n=9,901) demonstrated a 15% reduction in the composite renal outcome (sustained macroalbuminuria, eGFR decline, renal death), extending prior data from LEADER and SUSTAIN-6. A notable fraction of the renal benefit appeared to be independent of glycaemic control, consistent with direct anti-inflammatory and antioxidant effects on the kidney[43, 44].

4) Adipose Tissue

Adipose tissue inflammation, characterized by crown-like structures of macrophages surrounding dead adipocytes, elevated MCP-1 and leptin levels, and reduced adiponectin levels, is a key driver of insulin resistance and systemic inflammation in obesity. GLP-1RAs reduce adipose macrophage infiltration, shift adipose tissue macrophages from M1 to M2 phenotype, and restore adiponectin secretion by 15–25%. Adipocyte ROS are reduced through improved mitochondrial function and attenuated lipid peroxidation, effects associated with improved insulin Signalling (IRS-1 Ser→Tyr phosphorylation ratio) and GLUT4 translocation[45, 46].

5) Brain and Neurodegenerative Disease

The neuroprotective potential of GLP-1RAs represents a rapidly evolving area of investigation. GLP-1Rs expressed on dopaminergic neurons, microglia, and hippocampal neurons mediate anti-apoptotic and anti-inflammatory effects. In murine MPTP models of Parkinson's disease, liraglutide reduced microglial NF-κB activation and IL-6 secretion in the substantia nigra by 40–60%, while preserving tyrosine hydroxylase-positive neuronal density and improving motor function. Semaglutide similarly reduced amyloid-β-induced ROS and tau phosphorylation in 5xFAD Alzheimer's mice. Clinical trials of semaglutide in mild cognitive impairment (EVOKE) and Parkinson's disease (NCT04154072) are ongoing, with early biomarker data suggesting reductions in CSF IL-6 and 8-isoprostane[47, 48].

6) Pancreatic Beta Cells

Beta-cell loss in T2DM is mediated in part by IL-1β-induced apoptosis, ER stress, and mitochondrial ROS. GLP-1RAs exert direct beta-cell protective effects through: inhibition of NLRP3-derived IL-1β in islet macrophages, CREB-dependent upregulation of anti-apoptotic genes (BCL-2, BCL-XL, MCL-1), improvement of mitochondrial quality, and reduction of ER stress-induced CHOP expression. These effects collectively preserve beta-cell mass and function in animal models of T2DM, with clinical correlates including preserved C-peptide response and improved beta-cell function indices (HOMA-B) after liraglutide and semaglutide treatment[49, 50].

1) Inflammatory Biomarkers

High-sensitivity C-reactive protein (hsCRP), an acute-phase reactant driven by hepatic IL-6 signalling, is the most widely assessed inflammatory biomarker in GLP-1RA clinical trials. Across 14 randomized controlled trials (n > 18,000 patients), liraglutide and semaglutide consistently reduced hsCRP by 20–40% relative to placebo, with the magnitude of reduction correlating with weight loss in some but not all analyses, suggesting a weight-independent component. TNF-α reductions of 10–30% and IL-6 reductions of 15–35% have been documented in shorter-duration metabolic studies, while adiponectin, an anti-inflammatory adipokine inversely related to obesity, increases 15–25% with liraglutide treatment. Notably, the LEADER trial reported  

significant reductions in hsCRP and fibrinogen at 36 months of liraglutide treatment, with post hoc analyses suggesting that patients with higher baseline hsCRP levels derived proportionally greater MACE benefit, implicating baseline inflammatory burden as a modifier of cardiovascular efficacy[38, 51].

2) Oxidative Stress Biomarkers

Circulating MDA (malondialdehyde, assessed by TBARS assay) and urinary 8-isoprostane (a stable prostaglandin-like compound produced by free radical-mediated lipid peroxidation) represent the most clinically validated oxidative stress markers. In T2DM patients treated with liraglutide for 24–52 weeks, MDA fell by 25–45% and 8-isoprostane by 20–40%, with parallel increases in SOD and GPx activity (10–30%). Urinary 8-OHdG, a marker of oxidative DNA damage particularly relevant to DKD, was significantly reduced in a prospective study of liraglutide in T2DM patients with early nephropathy (−32%, p<0.001), with reductions correlating with preserved eGFR trajectory[38, 51].

Key priority research directions identified in this review include the need for tissue-specific mechanistic studies using human biopsy samples (such as liver, adipose tissue, and coronary arteries) to validate the in vivo engagement of pathways such as Nrf2, NF-κB, and NLRP3. There is also a need for head-to-head randomized controlled trials comparing anti-inflammatory biomarker profiles among GLP-1 receptor agonists while controlling for equivalent weight loss. Further, dedicated clinical trials should explore the role of GLP-1RAs in non-diabetic inflammatory conditions, including NASH, Parkinson's disease, and inflammatory arthritis, with clearly defined mechanistic endpoints such as Nrf2 activation, NLRP3 activity, and macrophage polarization. Additionally, combination strategies involving GLP-1RAs with agents like NLRP3 inhibitors (e.g., colchicine, MCC950) or Nrf2 activators (e.g., bardoxolone methyl) should be investigated to determine whether their effects are additive or redundant. Pharmacogenomic studies are also essential for identifying genetic variations in GLP-1R Signalling pathways that may influence individual anti-inflammatory responses. Finally, further research is needed to determine optimal dosing and timing strategies to maximize anti-inflammatory benefits, including whether these effects persist at lower glycemia-equivalent doses or require higher, dose-dependent exposure[26, 52-54].

Although GLP-1 receptor agonists demonstrate significant anti-inflammatory and antioxidant benefits, concerns remain regarding the long-term consequences of chronic immune modulation. Prolonged suppression of inflammatory pathways may potentially alter normal immune responses and increase susceptibility to infections or immune imbalance in susceptible individuals. Common adverse effects, such as gastrointestinal intolerance (nausea, vomiting, and diarrhoea), may also affect long-term adherence. In addition, rare concerns related to pancreatitis, gallbladder disease, and pancreatic safety continue to require careful monitoring. Current evidence regarding long-term immunological safety is still limited, particularly in non-diabetic populations receiving higher-dose therapy for obesity or chronic inflammatory conditions. Therefore, further long-term clinical and mechanistic studies are necessary to establish the safety and tolerability profile of GLP-1RAs during chronic use[55, 56].

In conclusion, GLP-1 receptor agonists represent a unique therapeutic class that extends beyond glycaemic control to exert significant anti-inflammatory and antioxidant effects through coordinated modulation of NF-κB, NLRP3, and Nrf2 pathways. These pleiotropic mechanisms contribute to their demonstrated benefits across cardiovascular, hepatic, renal, and neurological conditions. As evidence continues to evolve, the anti-inflammatory pharmacology of GLP-1RAs may prove to be as important as their metabolic actions, supporting their expanding role in the management of complex chronic diseases.

Summary: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly recognized for their therapeutic effects beyond glycaemic control in type 2 diabetes mellitus and obesity. This review comprehensively summarizes the anti-inflammatory and antioxidant mechanisms of GLP-1RAs, focusing on their modulation of key molecular pathways, including NF-κB, NLRP3 inflammasome, and Nrf2/Keap1 signaling. Through activation of cAMP/PKA and PI3K/Akt pathways, GLP-1RAs reduce pro-inflammatory cytokine production, suppress oxidative stress, improve mitochondrial function, and enhance endogenous antioxidant defenses. The review further highlights organ-specific protective effects in the cardiovascular system, liver, kidneys, adipose tissue, brain, and pancreatic beta cells, supported by biomarker-based clinical and preclinical evidence. Additionally, emerging therapeutic implications in non-alcoholic steatohepatitis, chronic kidney disease, neurodegenerative disorders, and cardiovascular risk reduction are discussed. Overall, this review provides an integrated mechanistic and translational perspective on the pleiotropic actions of GLP-1RAs and emphasizes their potential role in managing chronic inflammatory and oxidative stress-related diseases.

Data Availability statement: Not Applicable.

Ethics statement: No direct interactions with human or animal subjects were involved. Therefore, ethical approval 

and informed consent were not required.

Funding: No funding or sponsorship was received for this study.

Conflict of interest: Authors declare no conflict of interest.