Non-steroidal anti-inflammatory drugs on metabolic dysfunction-associated steatotic liver disease: From molecular mechanisms to potential clinical applications

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Data may be preliminary. 13 January 2025 V1 Latest version Share on Non-steroidal anti-inflammatory drugs on metabolic dysfunction-associated steatotic liver disease: From molecular mechanisms to potential clinical applications Authors : yingying xiang , Wei Qian , Guang Ji , and Li Zhang 0000-0002-5338-6096 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.173676616.66842415/v1 682 views 216 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The rising prevalence of metabolic dysfunction related fatty liver disease (MASLD) is related to the increased mortality and substantial health care costs, which constitutes a major global health challenge. Currently, effective treatment options for MASLD is still in need. Metabolic inflammation is a typical feature of MASLD. Management of metabolic inflammation represents a significant strategy for the treatment of MASLD. Non-steroidal anti-inflammatory drugs (NSAIDs), known for their anti-inflammatory and analgesic properties, are widely used in various inflammatory diseases. Recent clinical investigations revealed that certain NSAIDs can prevent the progression of MASLD, which brings hope for the treatment of MASLD. However, concerns on the accurate application, as well as the potential mechanisms are still unknown. In this study, we summarized the update of NSAIDs in the treatment of MASLD, and systematically discussed their potential mechanisms in treating MASLD, aiming to provide new research directions for the management of MASLD. Non-steroidal anti-inflammatory drugs on metabolic dysfunction-associated steatotic liver disease: From molecular mechanisms to potential clinical applications Yingying Xiang a , Wei Qian b , Guang Ji a,c , Li Zhang a,c * a Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. b School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. C State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, China. * Corresponding author at: Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. E-mail address: [email protected] (L. Zhang). Word count: 7694 Acknowledgements: Not applicable. Conflict of interest statement: The work was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. Abstract: The rising prevalence of metabolic dysfunction related fatty liver disease (MASLD) is related to the increased mortality and substantial health care costs, which constitutes a major global health challenge. Currently, effective treatment options for MASLD is still in need. Metabolic inflammation is a typical feature of MASLD. Management of metabolic inflammation represents a significant strategy for the treatment of MASLD. Non-steroidal anti-inflammatory drugs (NSAIDs), known for their anti-inflammatory and analgesic properties, are widely used in various inflammatory diseases. Recent clinical investigations revealed that certain NSAIDs can prevent the progression of MASLD, which brings hope for the treatment of MASLD. However, concerns on the accurate application, as well as the potential mechanisms are still unknown. In this study, we summarized the update of NSAIDs in the treatment of MASLD, and systematically discussed their potential mechanisms in treating MASLD, aiming to provide new research directions for the management of MASLD. Keywords: non-steroidal anti-inflammatory drugs; metabolic dysfunction-associated steatotic liver disease; efficacy; mechanism; safety Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), encompasses a wide spectrum of liver injuries, ranging from hepatic steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis to MASLD-associated hepatocellular carcinoma (MASLD-HCC)(Rinella et al., 2023). MASLD has emerged as the most prevalent chronic liver disease globally, affecting over one-third of the adult population and serving as a major contributor to liver-related morbidity and mortality(Miao, Targher, Byrne, Cao & Zheng, 2024). Given the high prevalence of MASLD and its public health implications, it is crucial to develop effective management strategies for MASLD. Lifestyle interventions focusing on healthy nutrition and regular physical activity have been foundational in treatment. However, the effectiveness of these interventions are limited, and sustainability remains a challenge(Tincopa, Anstee & Loomba, 2024). Currently, a selective thyroid hormone receptor beta (THR-β) agonist, resmetirom, has been approved for the treatment of MASH with fibrosis, with less than 30% clinical efficiency. The development of new, safe, and effective therapeutic agents remains a critical topic, aligning with the diverse nature of MASLD and providing patients with more options. With the in-depth study of the pathogenesis of MASLD, more and more evidence suggest that immune response dysregulation is considered an important driving factor in the development of MASLD(Sawada, Chung, Softic, Moreno-Fernandez & Divanovic, 2023). Therefore, anti-inflammatory may become a possible strategy for the treatment of MASLD. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for various inflammatory diseases due to their anti-inflammatory effects. NSAIDs competitively inhibit the activity of cyclooxygenase (COX), blocking the production of prostaglandins (PGs) from arachidonic acid (AA), and disrupting the downstream inflammatory mediators’ biotransformation(Caronni & Ostuni, 2022). NSAIDs are often regarded as detrimental to mitochondrial function, thereby contributing to hepatic steatosis(Bessone, Dirchwolf, Rodil, Razori & Roma, 2018). Contrary to this traditional view, a recent randomized controlled trial (RCT) has shown the potential benefits of NSAIDs in MASLD management. It’s reported that low-dose aspirin, a representative NSAID, significantly reduced hepatic fat contents in adults with MASLD(Simon et al., 2024). Additionally, other NSAIDs such as α-L-guluronic acid, salsalate, sodium salicylate, indobufen, and nimesulide have been shown to significantly retard the progression of MASLD in animal models(Bai et al., 2024; Huang et al., 2023; Jung et al., 2013; Park, Wong, Guan, Oprescu & Giacca, 2007; Tsujimoto et al., 2016). Despite the positive effects of NSAIDs in MASLD management, their COX inhibitory effects may lead to side effects, such as gastrointestinal, renal, and cardiovascular side effects(Pereira-Leite, Nunes, Jamal, Cuccovia & Reis, 2017). Therefore, the benefits and risks of NSAIDs in the treatment of MASLD warrant reevaluation. Furthermore, exploring the mechanism of NSAIDs against MASLD and identifying promising NSAID candidates can provide new ideas and directions for the management of MASLD. Classification and mechanism of NSAIDs NSAIDs are commonly used in the clinical treatment of various inflammatory diseases, including aspirin, ibuprofen, acetaminophen, salsalate, indobufen, sodium salicylate, celecoxib, and nimesulide ( TABLE 1 ). NSAIDs can be classified into three categories based on their mechanism, and different categories may have distinct impacts on MASLD. Therefore, a thorough understanding of their classification and action is essential for assessing the potential role of NSAIDs in the treatment of MASLD. NSAIDs perform their anti-inflammatory actions primarily by inhibiting COX enzymes in either a selective or non-selective manner, effectively blocking the conversion of AA into PGs and thromboxane A2 (TXA2), which results in antipyretic, analgesic, and anti-inflammatory properties(Patrono & Baigent, 2014). There are two isoforms of COX enzymes: the constitutively expressed COX-1 isoform and the inducible COX-2 isoform. COX-1 is known as a “physiological enzyme,” found in various cells and tissues including endothelial cells, monocytes, gastrointestinal epithelial cells, platelets, and kidneys. It is crucial in regulating platelet activity, gastric mucosal protection, and maintaining renal blood flow. Conversely, COX-2 is termed a “pathological enzyme,” and its expression is upregulated in several cells and tissues, such as vascular endothelial cells, rheumatoid synovial endothelial cells, monocytes, and macrophages, under inflammatory conditions, resulting in the release of inflammatory PGs and exacerbating inflammatory damage(Rao & Knaus, 2008). The classification of NSAIDs according to their relative their relative inhibitory activities against two isoforms of COX enzymes can be categorized into the following groups: NSAIDs with the IC50 ratio (COX-2 IC50/COX-1 IC50) > 5 were classified as selective COX-1-inhibitors, those with the IC50 ratio between 0.2 and 5 were classified as non-selective COX inhibitors, and those with the IC50 ratio < 0.2 were classified as selective COX-2 inhibitors(Blain, Jouzeau, Netter & Jeandel, 2000). (1) selective COX-1 inhibitors, with 75-100 mg/d aspirin being the most commonly recognized selective COX-1 inhibitor, which are associated with a relatively low risk of gastrointestinal adverse effects; (2) non-selective COX inhibitors, including aspirin (>100 mg/d), ibuprofen, salsalate, acetaminophen, sodium salicylate, and indobufen, with a notably increased risk of gastrointestinal side effects from prolonged high-dose use. (3) selective COX-2 inhibitors, including celecoxib and nimesulide, which are associated with common cardiovascular side effects(Antman et al., 2007). Potential mechanisms of NSAIDs in the treatment of MASLD The occurrence and development of MASLD involve multiple molecular mechanisms, including the functions of immune cells, glucose and lipid metabolism, oxidative stress, hepatic hemodynamics, and adipokine secretion(Baffy & Bosch, 2022; Huby & Gautier, 2022; Lee, Korf & Vidal-Puig, 2023). Recent studies have demonstrated that NSAIDs exhibit immunomodulation, regulate glucose and lipid metabolism, inhibit oxidative stress, improve liver hemodynamics, and modulate adipokine secretion, which may hold significance in the management of MASLD. 3.1 Immunomodulatory Immune function is closely associated with the development of hepatic steatosis, fibrosis, cirrhosis, and HCC in MASLD(Sawada, Chung, Softic, Moreno-Fernandez & Divanovic, 2023). Inflammatory infiltration in the liver is a significant contributor to the progression of MASLD(Hammerich & Tacke, 2023). The inflammation of adipose tissue, an important metabolic organ, can disrupt metabolic functions and exacerbate the progression of MASLD through the adipose-liver axis(Lee, Wu & Lin, 2023). Current research has demonstrated that aspirin and nimesulide can inhibit inflammatory infiltration in the liver, and salsalate, celecoxib and indobufen can reduce inflammation in both liver and adipose tissues. Additionally, sodium salicylate may indirectly affect hepatic lipid accumulation by decreasing the level of inflammation in adipose tissue. Aspirin has been shown to inhibit inflammatory infiltration in liver tissue, reducing hepatic steatosis, fibrosis, and the incidence of HCC. The anti-inflammatory effects of aspirin was dose-dependent. Nuclear factor kappa-B (NF-κB) acts a critical transcription factor that directly regulates the expression of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α), playing a significant role in the modulation of inflammatory and immune responses(Huh & Saltiel, 2021). The efficacy of high-dose aspirin in MASLD was primarily through its inhibition of the liver NF-κB signaling pathway, which was responsible for the inflammatory response. It has been proved that 46.3 mg/d aspirin significantly reduced the expression of Mcp-1 and Il-8 mRNA in the livers of MASH guinea pigs(Ipsen et al., 2021). In type 2 diabetes mellitus (T2DM) rats, 120 mg/kg/d aspirin decreased liver expression of NF-κB p65, lowered serum TNF-α levels, and improved insulin resistance(Sun, Han, Yi, Han & Wang, 2011). Activation of angiotensin II type 1 receptor (AT1R) enhanced NF-κB expression, and aspirin inhibited inflammation by controlling the AT1R/NF-κB pathway(Chen et al., 2022). A dosage of 100 mg/kg/d aspirin reduced the expression of macrophage antigens and AT1R proteins and lowered TNF-α levels in liver tissue of the MASLD rabbits, leading to decreased hepatic steatosis and inflammation, possibly through inhibiting the AT1R/NF-κB/ peroxisome proliferator-activated receptor δ (PPARδ) pathway(Han et al., 2020). In a heterotopic mouse model of HCC, 75 mg/kg/d aspirin targeted the NF-κB/p65 and LMCD1-AS1/let-7g in the liver tissue, reducing prolyl-4-hydroxylase alpha polypeptide II (P4Ha2) mRNA and protein levels and decreasing the expression of collagen I, thereby inhibiting tumor growth(Wang et al., 2019). Furthermore, low-dose aspirin diminished the activation of Kupffer cells in MASH mice and reduced the infiltration of inflammatory myeloid cells(Malehmir et al., 2019). Sex differences influence innate immune responses, playing a significant role in the progression of MASLD(Booijink, Ramachandran & Bansal, 2024). The anti-inflammatory effects of low-dose aspirin were also modulated by animal’s sex. In male MASLD mice, a dosage of 3 mg/kg/d of aspirin activated c-jun N-terminal kinase (JNK) and NF-κB signaling in the liver, promoting inflammation and leading to impaired insulin sensitivity. In contrast, aspirin did not significantly affect JNK and NF-κB signaling in female MASLD mice but instead enhanced insulin signaling in the liver. Additionally, low-dose aspirin’s effects on HCC were impacted by sex. In female mice, low-dose aspirin inhibited p42/44 mitogen-activated protein kinase (MAPK) signaling, enhanced the expression of the liver tumor suppressor gene phosphatase and tensin homolog ( Pten ) and reduced DNA methylation affecting wingless-type MMTV integration site family (Wnt) signaling, thus suppressing liver cancer development. Conversely, in male mice, aspirin upregulated hepatic p38 MAPK phosphorylation, thereby promoting HCC occurrence(Zhou et al., 2019). Moreover, nimesulide has been shown to modulate hepatic immune responses and suppress liver collagen synthesis. Research indicated that for MASLD mice, nimesulide significantly reduced the number of Kupffer cells, inhibited the expression of Mcp-1 mRNA, and downregulated the expression of metalloproteinases-1 ( Timp-1 ) and Procollagen-1 mRNA in the livers(Tsujimoto et al., 2016). Salsalate has shown promising effects in modulating immune function in the liver and adipose tissue. On the one hand, salsalate improved MASLD by inhibiting the NF-κB pathway in liver tissue. It has been shown to downregulate NF-κB mRNA expression and decrease plasma MCP-1 levels in the livers of MASH mice(Liang et al., 2015). In vitro experiments further indicated that salsalate inhibited lipid accumulation and impaired lipid metabolism in HepG2 cells in a dose- and time-dependent manner. This effect might be attributed to salsalate’s inhibition of Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK)-mediated NF-κB activation, which reduced the binding activity of NF-κB to the fetuin-A promoter, thereby decreasing Fetuin-A mRNA expression and secretion(Jung et al., 2013). On the other hand, inflammatory infiltration in adipose tissue can influence the progression of MASLD through the adipose-liver axis. Salsalate suppresses inflammatory responses in adipose tissue, ameliorating metabolic dysregulation and reducing hepatic lipid deposition. It effectively lowered triglyceride and cholesterol concentrations in the livers, while decreasing Ccl2 mRNA expression in both liver and adipose tissue and reducing serum levels of MCP-1 and TNF-α in non-obese hereditary hypertriglyceridemic (HHTg) rats(Huttl et al., 2023). In MASLD mice, intraperitoneal injection of salsalate reduced macrophage infiltration in both liver and adipose tissues, lowered Il-1β, Il-6 , and Tnf-α mRNA levels in adipose tissue, and reversed the activation of caspase-6 in the liver, leading to reduced hepatic lipid content(Li, Chen, Zhang, Bi, Yang & Li, 2021). For MASH mice, celecoxib not only improved pathological changes in the livers but also downregulated COX-2 mRNA and protein expressions in the liver tissue while decreasing serum levels of TNF-α and prostaglandin E2 (PGE2)(Wu et al., 2016; Zhu et al., 2022). It may alleviate liver inflammation by inhibiting protein kinase B (AKT). Celecoxib shows potential in the treatment of MASLD by modulating the adipose-liver axis. Research has shown that celecoxib improved hepatic steatosis in MASLD mice with AKT overexpression, suppressing PGE2 production and reducing the release of IL-1β, IL-6, and TNF-α in the liver (Zhang et al., 2022). In HCC, celecoxib inhibited PGE2 synthesis in the livers of HCC mice with AKT/c-Met overexpression. In vitro experiments have further confirmed the anti-inflammatory effects of celecoxib in HCC, significantly reducing PGE2 release induced by AKT/c-Met in HepG2 cells(Qiu et al., 2019). Additionally, celecoxib exerts anti-inflammatory effects and reduces steatosis by modulating the adipose-liver axis. In social submissiveness (Sub)-obese mice, celecoxib improved the degree of hepatic steatosis while decreasing Mcp-1 mRNA expression in adipose tissue(Ben-Shachar et al., 2023). In metabolic syndrome mice, celecoxib reduced hepatic triglyceride levels and decreased macrophage infiltration in adipose tissue, leading to lower TNF-α levels in epididymal white adipose tissue (eWAT) and reduced TNF-α and MCP-1 levels in the subcutaneous white adipose tissue (sWAT)(Lu, Hung & Hsieh, 2016). Indobufen also influences the progression of MASH through the adipose-liver axis. Indobufen improved hepatic steatosis, inflammatory cell infiltration, liver fibrosis, and liver injury in MASH animals, which were closely associated with its upregulation of suppressor of IKBKE 1 (SIKE) expression in both liver and white adipose tissue (WAT), reduction of the interaction between SIKE and TGF-beta activated kinase 1 (TAK1), and inhibition of the activation of the JNK and p38 pathways in the liver(Bai et al., 2024). Sodium salicylate mitigates inflammation in adipose tissue, indirectly reducing the degree of hepatic steatosis. While sodium salicylate decreased lipid accumulation in the liver, it also reduced the recruitment of pro-inflammatory M1 macrophages to eWAT, lowered the expression of Mcp-1 and Saa3 mRNA in eWAT, and reversed the increase in IL-1β levels secreted by adipose-derived stromal vascular fraction (SVF) cells stimulated with lipopolysaccharide (LPS) + adenosine triphosphate (ATP)(Kajani et al., 2022). However, the mechanism by which sodium salicylate prevents MASLD through the reduction of inflammation in adipose tissue remains unclear and warrants further investigation. 3.2 Regulation of glucose and lipid metabolism Dysregulation of glucose and lipid metabolism is a crucial factor in the pathogenesis of MASLD, with insulin resistance serving as a key mechanism driving this dysregulation(Jung, Koo & Lee, 2024; Yan, Man, Ma & Gao, 2022). NSAIDs have been investigated for their potentials to ameliorate metabolic disorders and are considered potential treatments for MASLD. Both salsalate and sodium salicylate have been shown to improve insulin resistance; aspirin, celecoxib and α-L-guluronic acid could improve MASLD by regulating the multi-organ glucolipid metabolism. Insulin resistance in extrahepatic organs, including skeletal muscle and adipose tissue, contributes to the progression of MASLD via crosstalk between multi-organ crosstalk(Su et al., 2022). Salsalate enhances insulin sensitivity across multiple organs, including skeletal muscle and adipose tissue. In HHTg rats treated with salsalate, eWAT and skeletal muscle exhibited increased sensitivity to insulin, along with increased lipolytic activity in eWAT, and reduced triglyceride content in skeletal muscle. Meanwhile, in the liver tissue of HHTg rats, salsalate enhanced the expression of cytochrome P450 proteins involved in lipid metabolism, including cytochrome P450 4a1 (Cyp4a1), Cyp4a2, and Cyp4a3. It also decreased the mRNA expressions of lipogenesis-related genes and enzymes involved in cholesterol synthesis, such as fatty acid synthase ( Fasn ) and serol regulatory element binding protein 1 ( Srebp1 ) , 3-hydroxy-3-methylglutaryl-CoA reductase ( Hmgcr ), and low-density lipoprotein receptor ( Ldlr ) , along with increased the expression of ATP binding cassette transporter G5 (Abcg5 ), which encoded for cholesterol transport proteins in the liver membrane in the livers of HHTg rats(Huttl et al., 2023). In obese mice, the insulin-sensitizing effects of salsalate on adipose tissue were further confirmed, as it stimulated insulin signaling in the eWAT, with the upregulation of p-Akt and p-glycogen synthase kinase-3 β (GSK-3β) expression(Nie et al., 2017). Additionally, salsalate influences lipid metabolism in the liver, skeletal muscle, and adipose tissue, involving lipogenesis, cholesterol metabolism and transport, lipolysis, and β-oxidation. On the one hand, salsalate activated the hepatic AMPK pathway, thereby inhibiting lipogenesis and improving hepatic steatosis. Administration of salsalate promoted AMPK expression in the livers of MASLD animals, inhibited mammalian target of rapamycin (mTOR) phosphorylation, and downregulated mRNA expression of lipogenesis-related genes, including peroxisome proliferator activated receptor gamma ( Ppar-γ ), CCAAT/enhancer binding protein alpha (Cebpα), sterol regulatory element binding transcription factor 1( Srebp-1c ), and aP2(Li, Chen, Zhang, Bi, Yang & Li, 2021) . In vitro studies have further demonstrated that salsalate inhibited mTOR phosphorylation and SREBP-1c expression in HepG2 cells, thereby alleviating steatosis(Jung et al., 2013). On the other hand, salsalate can improve liver steatosis by promoting thermogenesis in liver, skeletal muscle, and adipose tissue. In AMPK-β1 knockout mice, salsalate increased VO2, reduced fasting blood glucose levels, improved glucose tolerance, and led to decreased hepatic lipid content(Smith et al., 2016). In MASH mice, salsalate administration upregulated β-oxidation-related mRNA expression of Ppar-α , peroxisome proliferator-activated receptor gamma coactivator 1-beta (Pgc-1β) , and retinoid X receptor alpha (Rxr-α) , and inhibited the primary transcription factor for triglyceride synthesis, carbohydrate response element binding protein (ChREBP), thus reducing lipogenesis(Liang et al., 2015). Additionally, feeding high-fat diet (HFD) mice with 0.5% salsalate activated mitochondrial uncoupling and the sarcolipin (Sln)/sarcoplasmic reticulum Ca2+- ATPase 2a (Serca2a) axis in skeletal muscle tissue, thereby enhancing the expression of mRNAs related to glucose and fatty acid transport, lipolysis and oxidation, glycolysis, and the tricarboxylic acid cycle. Mitochondrial uncoupling and electron transport mRNA expressions were upregulated, leading to enhanced thermogenesis in skeletal muscle, although thermogenesis in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) showed no significant difference(Nie et al., 2017). However, Brennan K. Smith et al. found that a dosage of 2.5 g/kg/day salsalate could stimulate thermogenesis in brown adipose tissue independent of uncoupling protein 1 (UCP-1) in T2DM mice with MASLD(Smith et al., 2016). Hesham Shamshoum et al. confirmed that 2.5 g/kg/day salsalate increased the expression of thermogenesis-related mRNA such as acyl-CoA oxidase 1 ( Acox1 ) and carnitine palmitoyltransferase 1A ( Cpt1a ) in mice with olanzapine-induced hepatic fat accumulation(Shamshoum, Medak, McKie, Jeromson, Hahn & Wright, 2023). This discrepancy may be due to variations in the administered dose of salsalate and the disease status. Dysregulation of hepatic gluconeogenesis can lead to abnormal lipogenesis and promote hepatic steatosis(Onyango, 2022). Salsalate has been shown to inhibit aberrant hepatic gluconeogenesis, significantly lowering the mRNA expression of Glucose-6-phosphatase glucose-6-phosphatase ( G6pc) and phosphoenolpyruvate carboxykinase 1 (Pck1) in obese mice, as well as reducing G6Pase and phosphoenolpyruvate carboxykinase (PEPCK) protein levels. Moreover, in vitro studies have further confirmed that salsalate suppressed gluconeogenesis, decreasing G6pc and Pck1 mRNA expression in fasting HepG2 cells(Nie et al., 2017). Likewise, sodium salicylate enhance insulin sensitivity in the liver and skeletal muscle, which is influenced by the timing of administration. Edward Park et al. reported that sodium salicylate reduced the levels of IkappaB-α (IκB-α) in the liver and skeletal muscle tissues of short-term intralipid plus heparin (IH)-induced insulin-resistant rats, reversing insulin resistance in these tissues(Park, Wong, Guan, Oprescu & Giacca, 2007). Conversely, Sandra Pereira et al. found that long-term IH infusion did not activate liver IKKβ in insulin-resistant rats; sodium salicylate prevented the rise in plasma free fatty acids (FFA) associated with peripheral insulin resistance but did not prevent hepatic insulin resistance(Pereira et al., 2013). The observed discrepancy is primarily attributed to variations in the duration of the experimental model. Additionally, sodium salicylate preserved HDL-mediated cholesterol efflux (HDL-CEC) and inhibited cholesterol accumulation in plasma and liver of obese mice. Proteomic analysis of liver tissue indicated that sodium salicylate enhanced the expression of proteins involved in β-oxidation, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle(Kajani et al., 2022). Moreover, sodium salicylate inhibited gluconeogenesis in the liver of insulin-resistant rats, thereby improving glucose utilization(He, Zhao, Zhang, Li & Han, 2010). Aspirin modulates lipid metabolism in the liver, promoting β-oxidation, fatty acid metabolism, and cholesterol metabolism. Low doses of aspirin enhance β-oxidation in liver tissue. As shown in previous studies, 3 mg/kg/day aspirin treatment over 12 weeks increased the expression of PPAR-α and PPAR-γ in the livers of MASLD mice, thereby promoting hepatic β-oxidation. Additionally, in female MASLD mice, 3 mg/kg/day of aspirin activated AMPK signaling to further enhance liver β-oxidation(Zhou et al., 2019). In contrast, high doses of aspirin promoted energy production. Administration of 100 mg/kg/day aspirin elevated levels of oxidative phosphorylation biomarkers, such as PPARδ, AMPK, and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), in the liver of MASLD rabbits, increasing hepatic ATP levels. In vitro experiments revealed that treatment with 5 μM of aspirin for 24 hours reduced protein levels of FASN, which promoted fatty acid synthesis, and HMGCR, which affected cholesterol biosynthesis, in HepG2 cells (Han et al., 2020). Celecoxib reduces hepatic lipid deposition and inhibits the development of HCC by regulating the AKT signaling pathway. In MASLD mice with hepatic overexpression of Akt, as well as in HepG2 and Huh-7 cells, celecoxib has been shown to inhibit the AKT/mTORC1 signaling pathway and its downstream lipogenic processes. It reduced AKT Thr308 phosphorylation, thereby decreasing the phosphorylation of mTOR and ribosomal protein S6 (RPS6) and lowering the levels of lipogenic transcription factors such as FASN and acetyl-CoA carboxylase (ACC)(Zhang et al., 2022). Furthermore, celecoxib can modulate the AKT/FASN axis, inhibiting the development of HCC. It downregulated AKT Thr308 phosphorylation and RPS6 phosphorylation in HCC mice with liver-specific Akt/c-Met overexpression. In vitro experiments further confirmed that celecoxib inhibited AKT Thr308 phosphorylation and FASN expression in Huh-7 and SMMC-7721 cells in a concentration-dependent manner(Qiu et al., 2019). Cholesterol metabolism plays a critical role in the pathogenesis of MASLD(Li, Yu, Ou, Ouyang & Tang, 2021). α-L-Guluronic acid has been shown to significantly reduced plasma cholesterol levels, portal vein bile acid concentrations, and increased bile acid excretion in a dose-dependent manner in hypercholesterolemic rats(Idota et al., 2016). 3.3 Inhibition of oxidative stress Oxidative stress plays a significant role in the pathogenesis of MASLD(Fromenty & Roden, 2023). NSAIDs such as aspirin, salsalate, celecoxib, sodium salicylate, and nimesulide can inhibit oxidative systems, activate antioxidant systems, prevent liver damage, and improve MASLD. Aspirin alleviates oxidative stress in liver tissue by inhibiting COX-2 expression. NO-aspirin reduced the levels of lipid degeneration and inflammation in the liver of male rats with MASLD, accompanied by notable decreased in malondialdehyde (MDA) and nitric oxide (NO) in liver tissue, as well as significant reductions in the expression of COX-2 and inducible nitric oxide synthase (iNOS)(Ibrahim, Farghaly, Gomaa, Kelleni & Abdelrahman, 2011). Salsalate increased the mRNA expression of Glo1 , which encoded an enzyme involved in the degradation of methylglyoxal in HHTg rats, upregulating the activities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), while reducing levels of oxidized glutathione (GSSG) and lipid peroxidation parameters such as thiobarbituric acid reactive substances (TBARS) and conjugated dienes(Huttl et al., 2023). Celecoxib treatment not only inhibits the oxidative system in the serum and liver but also enhances the antioxidant system in these tissues in MASH mice. For MASH mice, celecoxib administration decreased MDA levels in the serum and liver, while increasing total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), catalase (CAT), and GSH-Px levels(Zhu et al., 2022). Sodium salicylate enhances the antioxidant system in liver and skeletal muscle tissues and inhibits oxidative systems. It increased GSH-Px activity in the liver and skeletal muscle of insulin-resistant rats while decreasing MDA levels and the concentrations of iNOS and NO in the liver(He, Zhao, Zhang, Li & Han, 2010; He, Zhao, Zhang, Li, Lu & Han, 2010). Additionally, nimesulide can inhibit the progression of hepatocellular carcinoma (HCC) by reducing levels of oxidative DNA damage in the liver. Nimesulide reduced 8-OHdG levels in the liver tissue of HCC rats in a dose-dependent manner, while also inhibiting precancerous lesions and tumor development(Denda et al., 2002). 3.4 Improvement of liver hemodynamics Portal hypertension, impaired vascular relaxation capacity, and abnormal platelet aggregation represent hemodynamic disturbances in the liver that are associated with lipid accumulation and ballooning degeneration in hepatocytes, serving as important factors in the pathogenesis of MASLD(Madir, Grgurevic, Tsochatzis & Pinzani, 2024). Aspirin and celecoxib affect the progression of MASLD through the improvement of liver hemodynamics (FIGURE 1). Aspirin has been shown to inhibit the progression of liver fibrosis via its anti-platelet aggregation effect. It has been shown to significantly reduce the fibrosis grade in liver fibrosis rats, along with prolonged prothrombin time and international normalized ratio (INR)(Li, Yang, Shi & Liu, 2017). Platelet-derived growth factor-B (PDGF-B), which is an important indicator of platelet activity, is a key pro-fibrotic cytokine(Wada, Tsuneki & Sasaoka, 2019). A dosage of 30 mg/kg/d aspirin reduced serum and liver PDGF-B levels in multidrug resistance protein2 (MDR2)-deficient mice, inhibited hepatic stellate cell (HSC) activation, and decreased portal and perisinusoidal fibrosis(Yoshida et al., 2014). However, a dosage of 46.3 mg/d of aspirin significantly lowered the expression of Pdgf-b mRNA in the liver of MASH guinea pigs, but did not have a significant effect on liver fibrosis(Ipsen et al., 2021). This discrepancy may be related to differences in species, disease models, and the dosage of aspirin administered. Additionally, low-dose aspirin reduced the interactions between platelets, liver endothelial cells, T cells, and innate immune cells in MASH mice through mechanisms independent of COX inhibition, thereby alleviating hepatic lipid deposition, fibrosis, and inflammatory infiltration(Malehmir et al., 2019). Increased intrahepatic vascular resistance led to tissue hypoxia, subsequently triggering the progression of MASLD(Hammoutene & Rautou, 2019). Celecoxib can enhance intrahepatic vascular function and lower intrahepatic vascular resistance, consequently suppressing the advancement of MASLD. In MASLD rats, celecoxib reduced the transhepatic pressure gradient (THPG) and downregulated the mRNA expression of genes related to prostaglandin receptors, such as Ptgs1, Ptgis, and Ptgs2(van der Graaff et al., 2022) . 3.5 Modulation of adipokine secretion Adiponectin and leptin are key adipokines. Elevated leptin levels may promote lipid deposition and inflammation in the liver, while adiponectin protects against these processes by reducing inflammation and improving metabolic functions, both of which are significant for the progression of MASLD(Polyzos, Kountouras & Mantzoros, 2016; Polyzos, Perakakis & Mantzoros, 2019). NSAIDs modulates the secretion of adipokines, thereby exerting an anti-MASLD effect. Sodium salicylate increased plasma adiponectin levels in insulin-resistant rats(Pereira et al., 2013). Salsalate upregulated adiponectin expression in the eWAT of obese mice, increasing plasma adiponectin concentrations while decreasing plasma leptin levels(Nie et al., 2017). Celecoxib, on the one side, increased serum adiponectin levels in MASH mice, while look the other way, it redistributed Adipo-R in liver, visceral adipose tissue and skeletal muscle, upregulated the mRNA and protein levels of Adipo-R1 and Adipo-R2 in the liver and visceral adipose tissue and downregulated Adipo-R1 and Adipo-R2 mRNA and protein levels in skeletal muscle(Zhu et al., 2022). Celecoxib also reduced serum leptin levels and eWAT leptin levels in mice with metabolic syndrome(Wu et al., 2016). 3.6 Others Apoptosis is present throughout the progression of MASLD and is one of the key factors influencing its progression(Xu et al., 2024). NSAIDs such as celecoxib and α-L-guluronic acid can modulate apoptosis, inhibiting hepatic steatosis, and reducing the incidence of HCC. Celecoxib alleviated the severity of hepatic steatosis in MASH mice while inhibiting the number of apoptotic cells in the liver through the Akt/p53 pathway(Wu et al., 2016). α-L-Guluronic acid acted synergistically with doxorubicin (DOX), enhancing the intracellular uptake and release of DOX in HCC mice, promoting immune responses, upregulating the M1 polarization of bone marrow-derived macrophages, facilitating the maturation of bone marrow-derived dendritic cells, and promoting tumor cell apoptosis(Huang et al., 2023). In vitro studies further demonstrated that α-L-guluronic acid promoted apoptosis in HepG2 cells in a dose- and time-dependent manner(Hassani, Afshari, Jafarnezhad-Ansariha & Mirshafiey, 2022). NSAIDs can influence the progression of MASLD by regulating the transforming growth factor-β (TGF-β). Salsalate prevented the development of liver fibrosis by downregulating TGF-β signaling. It inhibited the expression of liver fibrosis-related genes such as Timp-1 and ColA1 mRNA in MASH mice, reduced plasma TIMP-1 levels, and decreased liver Tgf-β mRNA expression(Liang et al., 2015). Furthermore, the activation of the extracellular regulated protein kinases (ERK) signaling pathway is an important factor contributing to the development of HCC(Moon & Ro, 2021). Celecoxib inhibited AKT/c-Met overexpression-induced phosphorylation of ERK Thr202/Tyr204 and the expression of proliferating cell nuclear antigen (PCNA), a proliferation-associated protein that responds during abnormal cell proliferation(Qiu et al., 2019). Clinical efficacy of NSAIDs in the treatment of MASLD Aspirin, α-L-guluronic acid, and salsalate have shown promising prospects in the treatment of MASLD, significantly improving its incidence and progression ( TABLE 2 ). 4.1 Aspirin Aspirin has been confirmed to reduce the risk of new-onset liver disease, chronic liver disease (CLD), and hepatic steatosis, slow down the progression of liver fibrosis progression, inhibit the transition from MASLD to HCC, and decrease mortality in the population with MASLD. Aspirin is effective in lowering the risk of new-onset liver disease and thus offers protective benefits for liver function. In population with MASH, a 30-month regimen of a combination pill containing 81 mg of aspirin significantly reduced serum alanine Aminotransferase (ALT) and aspartate aminotransferase (AST) levels(Merat et al., 2022). The risk of new-onset liver disease was notably reduced in previously healthy, non-HCC, non-alcoholic individuals who used aspirin regularly on a monthly basis. This protective effect was particularly significant in males, individuals below 60 years old, and those carrying certain genetic markers (PNPLA3 rs738409 [wt], TM6SF2 rs58542926 [wt], HSD17B13 rs72613567 [het], HSD17B13 rs72613567 [hom], MTARC1 rs2642438 [wt], and MTARC1 rs2642438 [het]). Moreover, the protective effect of aspirin against new-onset liver disease depended on the duration of aspirin intake. Individuals taking aspirin for more than 90 days saw a significantly reduced risk. For men, taking aspirin for over 360 days was correlated with a significant reduction in the risk of new liver disease(Vell et al., 2023). Furthermore, aspirin, can reduce the risk of CLD, although this effect is influenced by individual variability. In non-Hispanic Black or population consuming an alcohol intake of 1 drink/day, or aged 50 to 71 years old, the use of NSAIDs such as aspirin, was significantly associated with a decrease in CLD incidence. Notably, weekly aspirin usage reduced the risk of CLD to 50% among older adults aged 50 to 71. However, in older adults with a BMI ≥ 30 kg/m², a history of smoking, T2DM, and alcohol consumption >3 drinks/day, the use of NSAIDs such as aspirin, may paradoxically increase the risk of CLD(Sahasrabuddhe et al., 2012). Aspirin has been shown to alleviate hepatic steatosis, with its efficacy related to the frequency of use, dosage, duration and population heterogeneity. The age-specific effects of aspirin against hepatic steatosis were confirmed in a cross-sectional study. Monthly use of aspirin more than 15 times was associated with a lower prevalence of MASLD, particularly evident in males and individuals aged over 60 years old(Shen, Shahzad, Jawairia, Bostick & Mustacchia, 2014). Another cohort study further validated the gender-specific effects of aspirin in improving hepatic steatosis. Regular monthly use of aspirin significantly reduced the risk of developing MASLD and the MRI-diagnosed hepatic steatosis, with a more pronounced trend in males(Vell et al., 2023). Additionally, a randomized controlled trial further confirmed the role of aspirin in improving hepatic steatosis, showing that a daily dose of 81 mg for six months significantly reduced liver fat content in MASLD patients, particularly in those with stage 2 or higher liver fibrosis(Simon et al., 2024). In summary, the administration of aspirin at appropriate dosages, frequencies, and durations may reduce the risk of MASLD, especially in males, elderly individuals aged over 60 years old, and those with stage 2 or higher liver fibrosis. Aspirin can also impede the progression of liver fibrosis in MASLD patients. The use of aspirin was associated with reductions in composite liver fibrosis indices calculated by FIB4, APRI, Forns, and NFS, particularly in patients with chronic liver disease and MASH(Jiang et al., 2016). In MASLD patients, daily aspirin use significantly reduced the incidence of ballooning degeneration, lobular inflammation, MASH, fibrosis, and advanced fibrosis. For MASLD patients with stage 0-2 liver fibrosis, daily aspirin use for over two years significantly lowered the risk of progression to advanced fibrosis or cirrhosis(Simon et al., 2019). Cardiovascular disease (CVD) is a common extrahepatic complication of MASLD, and the presence of liver fibrosis further increases the risk of CVD and cardiovascular mortality(Targher, Byrne & Tilg, 2024). In patients with coronary artery disease, the use of antiplatelet agents such as aspirin was negatively correlated with liver fibrosis(Schwarzkopf et al., 2018). However, in patients with a history of myocardial infarction, oral administration of 1 g of aspirin daily for three years did not show significant changes in APRI, which may be related to the dosage of aspirin used; high doses of aspirin may adversely affect MASH patients(Tiwari-Heckler, Jiang, Popov & K, 2019). A cohort study found that 1300 mg of aspirin taken twice daily increased intestinal permeability in MASH patients, elevating serum endotoxin levels, which could initiate a cascade of necrotizing inflammation in hepatocytes, promoting the progression of liver fibrosis(Farhadi et al., 2008). Additionally, older adults are a population with a high incidence of myocardial infarction, and age may also be an important factor affecting the antifibrotic effects of aspirin(Bhatt, Lopes & Harrington, 2022). Thus, low-dose aspirin can improve liver fibrosis levels in patients with chronic liver disease, MASLD with stage 0-2 fibrosis, MASH, and coronary artery disease. However, the anti-fibrotic effect of aspirin is limited in elderly MASLD patients with a history of myocardial infarction. Aspirin has been found to reduce the risk of HCC. The use of aspirin and other NSAIDs significantly lowered the incidence of HCC in elderly individuals aged 50 to 71 years old, particularly among females and those consuming 2-3 alcoholic drinks per day. Specifically, monthly aspirin use can reduce the risk of HCC in elderly individuals aged 50 to 71 by 45%(Sahasrabuddhe et al., 2012). Using less than 163 mg of aspirin daily lowered the risk of HCC, and the duration of aspirin use didn’t affect this anti-HCC effect(Petrick et al., 2015). However, another cohort study conducted in MASLD patients reported contrasting results, indicating that aspirin treatment for 90 days or more was associated with a reduced risk of HCC(Lee, Hsu, Ho, Lin, Chen & Wu, 2023). Moreover, the dosage of aspirin that reduces HCC incidence is also a topic worth discussing. A cohort study found that weekly use of aspirin ≥ 325 mg reduced the risk of HCC, with this trend being more pronounced in females. For patients aged over 65 years old, with normal body weight, consuming less than 2 grams of alcohol daily and without T2DM, hypertension, or hyperlipidemia, using aspirin two or more times per week reduced the risk of HCC. This benefit was closely related to dosage and duration of use. Subjects who used more than 812.5 mg of aspirin weekly experienced a 51% reduction in HCC risk. Those who used it for over 10 years had a 45% risk reduction, while patients taking at least 243.75 mg of aspirin daily for five years or more saw a 59% decrease in HCC risk. Moreover, aspirin’s anti-HCC effect exhibited a carryover effect, as its protective role was no longer significant eight years after discontinuation(Simon et al., 2018). However, in non-cirrhotic MASLD patients, this anti-HCC effect was not statistically significant(Lee, Wu, Yu, Lin, Wu & Wu, 2017). Generally speaking, regular use of aspirin has an anti-HCC effect. However, this effect is influenced by various factors, including the patient’s age, gender, alcohol consumption, degree of liver cirrhosis, dosage and duration of aspirin. Additionally, aspirin use could lower mortality rates in MASLD patients, including overall mortality, CLD-related mortality and cardiovascular mortality. Among subjects with MASLD aged 45-59 years old, monthly use of aspirin 1-14 times was associated with a lower risk of overall mortality(Chen, Chen, Zeng, Yang & Li, 2023). This finding was corroborated by another cohort study, which showed that MASLD patients taking a compounded pill containing 81 mg of aspirin daily for five years had reduced rates of major cardiovascular events and cardiovascular mortality (Ramandi et al., 2023). However, this protective effect was influenced by ethnicity, as frequent aspirin use in non-Hispanic Black individuals with MASLD was associated with increased overall mortality(Chen, Chen, Zeng, Yang & Li, 2023). Finally, the disease state of MASLD may affect the pharmacokinetics of aspirin. Compared to patients with T2DM, those with MASLD and T2DM showed significantly reduced responsiveness to aspirin(Simeone et al., 2023). Therefore, careful consideration of MASLD patients’ responses to aspirin and other medications is essential when developing treatment plans to reduce potential risks and improve therapeutic efficacy. 4.2 α-L-Guluronic acid and salsalate α-L-Guluronic acid and salsalate have demonstrated certain effects in alleviating inflammation and improving metabolism. They have potential roles in the treatment of MASLD. Monocytes in peripheral blood mononuclear cells (PBMCs) are important participants in the development and progression of MASH. Inhibiting the inflammatory response in PBMCs from MASH patients may improve disease progression(Casari, Siegl, Deppermann & Schuppan, 2023). α-L-Guluronic acid significantly reduced the levels of inflammation in MASH patients. Treatment with 25 μg/ml α-L-guluronic acid for 18 hours in PBMCs from MASH patients leads to a significant downregulation of Tlr4 and NF-κB mRNA expression and a reduction in the secretion of IL-6 and TNF-α(Tahmasebi, Neishaboori, Jafari, Faghihzadeh, Esmaeilzadeh & Mirshafiey, 2021). However, there is currently no direct clinical evidence demonstrating its effects on the histopathological changes in MASH patients. As a potential therapeutic agent for MASH, α-L-guluronic acid warrants further investigation into its therapeutic effects. Although salsalate has been shown to have positive effects on metabolism, current research indicated that it didn’t significantly impact the degree of hepatic steatosis. For instance, in patients newly diagnosed with diabetes or prediabetes, the administration of 750 mg of salsalate twice daily for one month did not result in significant improvements in biochemical markers of MASLD(Faghihimani, Amini, Adibi, Naderi, Toghiani & Adibi, 2013). Additionally, a randomized controlled trial (RCT) involving obese Hispanic patients found that the intake of 2 g of salsalate twice daily for four weeks significantly improved glucose metabolism, increased serum adiponectin levels, and reduced IL-1β expression in adipose tissue, but there were no significant changes in liver fat content(Alderete et al., 2015). Salsalate may improve glucose metabolism by influencing adipose tissue function. It has been observed to reduce the levels of Hsd11b1 mRNA in sWAT in healthy males, affecting the activity of 11β-HSD1 in adipose tissue, but there were no significant changes in liver fat content (Nixon et al., 2012). Given the critical role of adipose tissue in the development of MASLD, further research is needed to explore the effects of higher doses and longer durations of salsalate treatment in patients with MASLD(Colella & Ramachandran, 2024). 4.3 Others NSAIDs may reduce the risk of mortality associated with CLD. In a population of elderly individuals aged 50 to 71 years old, monthly use of non-aspirin NSAIDs such as ibuprofen, has been linked to a decreased risk of death from CLD(Sahasrabuddhe et al., 2012). However, some studies indicated that ibuprofen may increase the risk of MASLD without promoting the progression from isolated hepatic steatosis to liver fibrosis or HCC. A cohort study found that the use of ibuprofen and COX-2 inhibitors wasn’t associated with the incidence of new-onset liver disease(Vell et al., 2023). Conversely, daily prescribed doses of NSAIDs were associated with a 3% increase in the risk of developing MASLD among patients with rheumatoid arthritis(Meng, Chen, Chen, Huang & Chen, 2024). Additionally, a cross-sectional study confirmed that the use of NSAIDs, including ibuprofen, promoted the occurrence of MASLD, revealing that using ibuprofen more than 15 times per month was associated with an increased prevalence of MASLD. Meanwhile, this study also reported that ibuprofen use didn’t not elevate the risk of progression to liver fibrosis or HCC in MASLD patients(Shen, Shahzad, Jawairia, Bostick & Mustacchia, 2014). Similarly, in populations with chronic liver diseases, including MASLD, the use of ibuprofen and other NSAIDs was not associated with an increased risk of liver fibrosis(Jiang et al., 2016; Simon et al., 2019). Jessica L. Petrick et al. also reported that ibuprofen usage didn’t increase the risk of HCC in the general population(Petrick et al., 2015). Acetaminophen can exacerbate MASLD, increasing the risks of MASH, liver fibrosis, and cirrhosis, while not promoting the progression of MASLD to HCC. In MASLD patients, the use of acetaminophen and other non-opioid analgesics was associated with higher rates of MASH and cirrhosis(Moon et al., 2021). The relationship between acetaminophen usage and HCC risk was not significant(Simon et al., 2018). Additionally, the disease stages of MASLD can influence the pharmacokinetics of acetaminophen. After administering 5 mg/kg of acetaminophen, MASLD children showed elevated serum and urinary levels of APAP-G(Barshop, Capparelli, Sirlin, Schwimmer & Lavine, 2011). After a 1000 mg dose of acetaminophen, MASH children exhibited markedly higher serum and urinary levels of APAP-gluc than normal participants, with increased expression of liver MRP3 and altered localization of MRP2 potentially representing the mechanisms by which MASH affects acetaminophen pharmacokinetics(Canet et al., 2015). In conclusion, patients with MASLD should exercise caution when using ibuprofen, acetaminophen, and other NSAIDs. While NSAIDs may reduce the risk of mortality from CLD under certain conditions, the potential for ibuprofen and acetaminophen to increase the risk of MASLD progression highlights the necessity for careful selection of NSAIDs based on individual patient profiles in clinical practice. Clinical safety of NSAIDs in treating MASLD Inappropriate use of NSAIDs may have adverse effects on the gastrointestinal tract, cardiovascular system, kidneys, and auditory system.(Pereira-Leite, Nunes, Jamal, Cuccovia & Reis, 2017) As potential therapeutic agents for MASLD, NSAIDs hold important clinical significance, yet their administration must be conducted cautiously to balance patient benefits against potential risks. 5.1 Adverse events Gastrointestinal adverse effects are among the most common side effects associated with aspirin. Retrospective cohort studies indicated that aspirin didn’t increase the risk of digestive ulcer bleeding in patients with MASLD (Simon et al., 2019; Vell et al., 2023) . In contrast, an RCT focused on low-dose aspirin therapy for MASLD reported a single case of heartburn, with no statistically significant difference compared to the control group. Additionally, this RCT identified potential adverse events from low-dose aspirin treatment for MASLD, including upper respiratory infections, joint pain, muscle pain, other infections, fever, dizziness, nausea, tachycardia, sensory abnormalities, and kidney stones, although these did not exhibit an increased risk compared to the control group (Simon et al., 2024) . Salsalate may cause tinnitus, although this symptom generally resolves within two weeks. A daily dose of 3 g of salsalate led to tinnitus in healthy males (Nixon et al., 2012) , while a dose of 4 g per day may result in tinnitus in obese adults, with symptoms subsiding within 1–2 weeks after continued dosing (Alderete et al., 2015) . Compared to aspirin, salsalate may has less irritating to the stomach. Currently, clinical studies have not reported gastrointestinal reactions associated with salsalate treatment for MASLD. Given that gastrointestinal are common adverse effects of NSAIDs, larger-scale, long-term prospective clinical trials are needed to verify the safety of salsalate in the treatment of MASLD. Overall, reports on the clinical safety of NSAIDs in the treatment of MASLD are relatively scarce, primarily focusing on aspirin and salsalate. Although both aspirin and salsalate demonstrate some potential in the management of MASLD, the existing clinical evidence is insufficient to comprehensively assess the long-term safety and potential risks associated with their use. Therefore, future RCTs and long-term observational studies are necessary to clarify the safety of NSAIDs in the treatment of MASLD. Such studies will provide more reliable evidence for clinical practice. 5.2 Risks and recommendations for the usage of NSAIDs For patients with MASLD, clinicians must consider the specific clinical condition of the patient, the pharmacokinetic characteristics of the medications, and potential drug interactions to develop an individualized treatment plan. Additionally, regular monitoring of the patient’s drug response and assessment of drug efficacy and safety are crucial for maximizing the therapeutic effects of NSAIDs while minimizing potential risks. Elderly patients, people with obesity, high cardiovascular risk, gastritis, impaired renal function, and those on multiple medications or with liver dysfunction are at a higher risk of experiencing adverse events when using NSAIDs. Therefore, it is particularly important to regularly evaluate drug efficacy and safety and adjust treatment plans accordingly. Aging can significantly affect drug pharmacokinetics and pharmacodynamics(Fialova et al., 2019; Novaes, da Cruz, Lucchetti, Leite & Lucchetti, 2017). For elderly patients, it is recommended to initiate treatment with the lowest possible dose and gradually titrate to the minimum effective dose. In obese patients, the increased adipose tissue may lead to a greater distribution of lipophilic drugs in fat tissue, consequently affecting the pharmacokinetics of these medications(Weiss, Krejcie & Avram, 2007). Thus, the expected duration of action for lipophilic NSAIDs such as salsalate and aspirin may be prolonged, necessitating cautious and timely administration in obese individuals. According to recommendations from the European League Against Rheumatism (EULAR), it is preferable to use naproxen, which has a lower risk profile, rather than diclofenac, which is associated with higher cardiovascular risk, in populations at increased cardiovascular risk(Agca et al., 2017). Furthermore, short-term (8-30 days) use of NSAIDs was associated with an increased risk of acute myocardial infarction(Ribeiro et al., 2022). For patients with gastritis, selective COX-2 inhibitors (celecoxib, e.g.) may be better options(Meara & Simon, 2013). In patients with impaired renal function, it is particularly important to select NSAIDs that have reduced renal excretion, such as indomethacin, diclofenac, and etodolac. Finally, for patients on multiple medications or with liver dysfunction, NSAIDs that undergo phase II biotransformation, such as indomethacin and diclofenac, may be safer alternatives(Davies & Skjodt, 2000). Conclusions NSAIDs are widely used in clinical practice due to their antipyretic and analgesic effect. Recent studies have revealed that NSAIDs possess additional benefits, including immunomodulation, regulation of glucose and lipid metabolism, inhibition of oxidative stress, improvement of liver hemodynamics, and modulation of adipokine secretion, making them potential candidates for the treatment of MASLD ( FIGURE 2 ). Understanding the efficacy and mechanism of NSAIDs in the treatment of MASLD can assist clinicians in developing more personalized treatment plans, ultimately improving patients’ quality of life. Through a review of the literature, we found that NSAIDs, such as aspirin, salsalate, and α-L-guluronic acid, demonstrate significant clinical efficacy in the treatment of MASLD. The clinical efficacy of NSAIDs in the treatment of MASLD is influenced by various factors, including the patient’s age, gender, comorbidities, nicotine and alcohol intake, the stages of MASLD, as well as the dosage, frequency, and duration of NSAIDs. The individual variability among patients can lead to markedly different effects of NSAIDs across different individuals. Therefore, to enhance the efficacy and safety of NSAIDs in the treatment of MASLD, clinical practice should involve a thorough assessment of each patient’s specific circumstances to devise personalized treatment strategies. This approach not only improves the management of MASLD but also enhances the quality of life for patients. Future research should focus on larger-scale and longer-duration clinical trials to explore the multiple factors influencing the efficacy of NSAIDs in the treatment of MASLD, thereby providing a more scientific and individualized basis for clinical treatment. Moreover, while various NSAIDs, including nimesulide, salsalate, celecoxib, indobufen, sodium salicylate, and α-L-guluronic acid, have demonstrated promising anti-MASLD effects in vitro and vivo studies, there is currently a lack of clinical research confirming the efficacy of these NSAIDs in patients with MASLD. The clinical application of NSAIDs in MASLD patients requires careful evaluation, and more clinical trials are needed to validate their efficacy and safety. Additionally, research on the mechanisms through which NSAIDs impact MASLD is still in preliminary stages. A comprehensive understanding of the mechanisms by which NSAIDs improve MASLD not only provides a theoretical basis for their clinical application but also guides the future development of more effective anti-MASLD medications, offering new treatment hopes for patients with MASLD. FUNDINGS This work was supported by the National Natural Science Foundation of China (82274448), and the Youth Science Discipline Leading Project of Science Commission (No.23XD1423700). AUTHOR CONTRIBUTIONS Y.X.: Writing – original draft. W.Q., G.J.: Writing – review & editing. L.Z.: Writing – review & editing, Investigation, Funding acquisition, Conceptualization. CONFLICT OF INTEREST STATEMENT The research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. ACKNOWLEDGMENTS Not applicable. DATA AVAILABILITY STATEMENT No data was used for the research described in the article. Reference： Agca R, Heslinga SC , et al. (2017). 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FIGURE 1 The alteration of liver hemodynamics upon non-steroidal anti-inflammatory drugs (NSAIDs). Materials provided by FigDraw (www.figdraw.com). FIGURE 2 Efficacy and mechanism of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Aspirin, nimesulide, salsalate, celecoxib, indobufen, sodium salicylate, and α-L-guluronic acid are common NSAIDs. These NSAIDs primarily exert their effects on the inhibition of hepatic steatosis, fibrosis, and hepatocellular carcinoma in MASLD through mechanisms such as immunomodulation, regulation of glucose and lipid metabolism, inhibition of oxidative stress, improvement of liver hemodynamics, and modulation of adipokine secretion. Materials provided by FigDraw (www.figdraw.com). 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Keywords anti-oxidants apoptosis cyclo-oxygenase cytokines drug discovery/target validation endocrine pharmacology hepatopharmacology inflammation metabolism nf-kappa-b nitric oxide nitric oxide synthase platelets/thrombocytes Authors Affiliations yingying xiang Longhua Hospital Shanghai University of Traditional Chinese Medicine View all articles by this author Wei Qian Shanghai University of Traditional Chinese Medicine View all articles by this author Guang Ji Longhua Hospital Shanghai University of Traditional Chinese Medicine View all articles by this author Li Zhang 0000-0002-5338-6096 [email protected] Longhua Hospital Shanghai University of Traditional Chinese Medicine View all articles by this author Metrics & Citations Metrics Article Usage 682 views 216 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation yingying xiang, Wei Qian, Guang Ji, et al. 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