Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over one-third of the global population, representing one of the most prevalent chronic liver diseases. The escalating global prevalence of MASLD is concerning, as the disease can progress silently to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Furthermore, MASLD is independently associated with increased risks of cardiovascular disease, chronic kidney disease, and various extrahepatic malignancies, posing a substantial threat to public health. Consequently, developing effective preventive and therapeutic strategies is crucial. L-carnitine is a well-established dietary supplement that demonstrates potential to mitigate the onset and progression of MASLD. Its proposed mechanisms include the enhancement of lipid metabolism, improvement of insulin sensitivity, stabilization of hepatocyte function, and reduction of inflammation, fibrosis, and tumorigenesis. This comprehensive review synthesizes recent advances in the molecular mechanisms through which L-carnitine influences MASLD pathogenesis and critically evaluates its therapeutic potential in MASLD prevention, management, and prognosis.
1 Introduction
The global prevalence of non-alcoholic fatty liver disease (NAFLD) has shown a consistent upward trend in recent decades, with current estimates indicating an overall prevalence of 30.05% (). Significant geographical variations exist. For instance, Latin America exhibits the highest prevalence (44.37%), followed by North Africa and the Middle East (36.53%). In contrast, Western Europe demonstrates the lowest prevalence (25.10%) (). The insidious disease progression presents substantial clinical challenges, as approximately 20–40% of NAFLD patients may develop non-alcoholic steatohepatitis (NASH) over several years (, ), which can subsequently advance to liver fibrosis and HCC (). NAFLD is independently associated with elevated risks of diabetes (), cardiovascular disease (), and chronic kidney disease (), collectively contributing to a growing global disease burden.
In a pivotal 2023 consensus statement, international liver associations proposed redefining disease terminology, replacing “NAFLD” with “metabolic dysfunction-associated steatotic liver disease (MASLD)” and “NASH” with “metabolic dysfunction-associated steatohepatitis (MASH)” (). This nomenclature shift aims to better reflect the underlying metabolic etiology, reduce stigmatization, and improve consistency in clinical trial enrollment. MASLD diagnosis requires hepatic steatosis plus at least one cardiometabolic risk factor. Although the MASLD definition differs conceptually from traditional NAFLD criteria, multiple validation studies demonstrate high diagnostic concordance between both classification systems (–). Therefore, this review consistently employs MASLD terminology.
MASLD pathogenesis involves complex interactions among multiple pathological processes, including excessive fatty acid accumulation, dysregulated inflammatory responses, oxidative stress, and insulin resistance. Carnitine, an essential molecule in cellular lipid transport, may ameliorate metabolic disturbances through various pathways, including regulating fatty acid metabolism, mitigating oxidative stress, and improving mitochondrial function. While existing reviews primarily focus on carnitine-lipid metabolism relationships, comprehensive analyses detailing its molecular roles across the MASLD spectrum remain limited. This review systematically synthesizes recent evidence regarding L-carnitine's effects on lipid metabolism, insulin sensitivity, hepatocyte function, and the inflammation-fibrosis axis, while discussing potential clinical applications and future research directions.
2 Carnitine
Carnitine (β-hydroxy-γ-trimethylaminobutyric acid) is a quaternary ammonium compound that functions as an essential cofactor in cellular energy metabolism. Its primary physiological role involves facilitating long-chain fatty acid transport across the inner mitochondrial membrane for β-oxidation. Carnitine exists as two stereoisomers: the biologically active L-carnitine and the pharmacologically inactive D-carnitine. Humans maintain carnitine homeostasis through dietary intake and endogenous synthesis, with estimated daily requirements of 0.3–1.9 mg/kg/day (). Approximately 75% of bodily carnitine derives from dietary sources, particularly red meat and dairy products, while the remaining 25% is synthesized endogenously (, ).
Endogenous carnitine biosynthesis utilizes lysine and methionine as primary substrates. Lysine provides the carbon backbone, while methionine contributes methyl groups via S-adenosylmethionine. This multi-step enzymatic process culminates with γ-butyrobetaine dioxygenase (γ-BBD) catalyzing the final conversion of γ-butyrobetaine to carnitine. As the rate-limiting enzyme, γ-BBD shows predominant expression in hepatic, renal, and cerebral tissues (). Importantly, impaired hepatic metabolic function can compromise carnitine biosynthetic capacity, potentially leading to relative deficiency that may contribute to hepatic lipid accumulation, inflammatory activation, oxidative stress, and insulin resistance.
Cellular carnitine utilization depends on active transmembrane transport mediated by organic cation transporter 2 (OCTN2). Encoded by solute carrier family 22 member 5 (SLC22A5), OCTN2 represents the principal high-affinity carnitine transporter in humans, facilitating cellular uptake in intestine, kidneys, skeletal muscle, heart, and liver. SLC22A5 mutations impair OCTN2 function, causing primary carnitine deficiency (PCD) (–), an autosomal recessive disorder characterized by skeletal myopathy, progressive cardiomyopathy, hypoglycemia, and hyperammonemia.
Beyond genetic determinants, OCTN2 expression and function undergo significant physiological and pharmacological regulation. Inflammatory conditions, particularly inflammatory bowel disease with elevated pro-inflammatory cytokines (TNF-α, IL-1β, IFN-γ), can suppress OCTN2 expression, reducing intestinal L-carnitine absorption (). Additionally, certain pharmacological agents, including cisplatin, downregulate renal OCTN2 expression, increasing urinary carnitine excretion and potential deficiency states (). Although these acquired “functional deficiencies” generally produce less severe effects than genetic mutations, they can significantly disrupt metabolic homeostasis in susceptible individuals.
Accumulating evidence indicates that appropriate L-carnitine supplementation has demonstrated beneficial effects in various pathological conditions. Documented benefits include improved insulin sensitivity in type 2 diabetes (), reduced inflammatory cytokines and short-term mortality in sepsis (), and ameliorated cardiac fibrosis in experimental heart failure models (). Consequently, maintaining adequate L-carnitine levels appears crucial for hepatic lipid homeostasis and systemic energy metabolism, and may also help attenuate liver inflammation and fibrosis progression. Given that L-carnitine represents the predominant biologically active form in humans, this review focuses specifically on its mechanisms and potential applications in MASLD.
3 Effects of L-carnitine on systemic metabolism
3.1 L-carnitine promotes fatty acid metabolism
The multifaceted mechanisms by which L-carnitine modulates metabolic dysfunction–associated steatotic liver disease are schematically summarized in Figure 1. One of the central metabolic actions of L-carnitine is the regulation of fatty acid metabolism in hepatocytes.
Figure 1
Fatty acid metabolism encompasses long-chain, medium-chain, and short-chain fatty acid processing, with carnitine playing an indispensable role in long-chain fatty acid catabolism. The carnitine-dependent transport system involves coordinated enzymatic reactions. Long-chain fatty acids are first activated to acyl-CoA esters in the cytosol. Carnitine palmitoyltransferase I (CPT1), located on the outer mitochondrial membrane, then catalyzes acyl transfer from acyl-CoA to carnitine, forming acylcarnitine. This reaction represents the primary rate-limiting step in fatty acid oxidation. The resulting acylcarnitine crosses the inner mitochondrial membrane via carnitine-acylcarnitine translocase (CACT). Within the mitochondrial matrix, carnitine palmitoyltransferase II (CPT2) regenerates acyl-CoA from acylcarnitine, releasing free carnitine for recycling. The acyl-CoA undergoes sequential β-oxidation, generating acetyl-CoA that enters the tricarboxylic acid (TCA) cycle for energy production or converts to ketone bodies in hepatic mitochondria (, ). This elaborate transport mechanism highlights the absolute dependence of long-chain fatty acid β-oxidation on carnitine availability, contrasting with medium-chain and short-chain fatty acids that enter mitochondria independently (, ).
Building on these mechanistic insights, Clinical observations support carnitine's metabolic relevance in fatty liver disease, as NASH patients show significantly reduced serum L-carnitine levels compared with healthy controls (). This carnitine deficiency appears progressive, with more pronounced reductions in patients having disease duration exceeding 5 years (), suggesting a potential pathophysiological role in disease progression.
Preclinical investigations consistently demonstrate that L-carnitine supplementation ameliorates metabolic disturbances in experimental NAFLD/NASH models. Multiple reports indicate that L-carnitine or carnitine-containing compounds reduce serum lipids and improve liver enzyme profiles in high-fat diet (HFD)-induced rodent models (–). Particularly insightful mechanistic evidence comes from a medaka fish NAFLD model, where metabolomic analysis revealed that L-carnitine not only reduced hepatic lipid deposition but also significantly elevated hepatic β-oxidation end products (acetyl-CoA and ATP) while upregulating antioxidant enzyme superoxide dismutase 2 (SOD2) (). These findings suggest a dual mechanism enhancing fatty acid catabolism while reducing oxidative stress. Preclinical evidence supporting these metabolic and regulatory effects of L-carnitine in MASLD, derived from animal and in vitro models, is summarized in Table 1.
Table 1
| Reference | Disease | Model (Sample size) | Duration | Dose | Outcomes |
|---|---|---|---|---|---|
| Sun et al. () | NAFLD | Mice, 70 (60/10) | 10 weeks | 0.2% to 4% L-carnitine in diet | ↓ TG, AST, ALT, body weight, liver weight, TNF-α, IL-6 ↑ IL-10 |
| Mollica et al. (47) | NAFLD | Mice, 30 (10/group) | 3 weeks | 200 mg/kg/day | ↓ lipid accumulation, ballooning ↓ROS, Cytochrome c, α-SMA, Caspase-2, NF-κB p65 ↑ PPARγ |
| Montesano et al. (43) | NAFLD | HepG2 cells, N/A | 48 h and 72 h | 5 mM L-carnitine | ↓ lipid accumulation, ROS ↑ AMPK activation, PGC1α, SOD2, Nrf2 |
| Ishikawa et al. (45) | NASH | Mice, 24 (8/group) | 8 weeks | 0.28% L-carnitine in diet | ↓ NAS and steatosis ↓ 8-OHdG, 4-HNE, TNF-α ↑ mRNA of Octn2, Cpt1a, Cpt2, Acadm, Sod2, Cat ↓ liver tumorigenesis |
| Amer et al. (59) | NASH | Mice, 36 (6/group) | 13 days | 300 or 500 mg/kg/day | ↓ NASH histology and serum liver enzymes ↓ hepatic oxidative stress and lipogenesis (SREBP-1) ↑ insulin signaling (increased p-Akt/Akt; decreased nuclear FOXO1) ↓ autophagy dysfunction, apoptosis, and necroptosis |
| Abd Eldaim et al. () | NAFLD | Mice, 56 (8/group) | 8 weeks (preventive)/10 weeks (therapeutic) | 200 mg/kg/day | ↓ TC, TG, ALT, AST, Ur, Cr, MDA ↑ GSH ↓ steatosis, ballooning degeneration, lobular inflammation, and apoptosis ↓ TNF-α, TGF-β1 |
| Lyu et al. (73) | MASH | Mice, Fibrosis:40 (10/group); HCC:102 (varies) | 20, 38, and 68 weeks (terminal endpoint) | 0.5% or 1% L-carnitine in diet | ↓ steatosis, inflammation, and fibrosis ↓ liver tumors ↓ EGR1/NEDD9/FAK/AKT pathway |
Animal and in vitro studies on L-carnitine supplementation in MASLD.
MASLD, metabolic dysfunction–associated steatotic liver disease; NAFLD, non–alcoholic fatty liver disease; NASH, non–alcoholic steatohepatitis; MASH, metabolic dysfunction–associated steatohepatitis. Notes on nomenclature: NAFLD and NASH correspond to MASLD and MASH, respectively, according to the current consensus.
Biochemical and histological parameters: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GSH, glutathione; MDA, malondialdehyde; NAS, NAFLD activity score; ROS, reactive oxygen species; TC, total cholesterol; TG, triglycerides; Ur, urea.
Proteins, cytokines, and signaling molecules (upright font): α-SMA, α-smooth muscle actin; Caspase−2; Cytochrome c; FOXO1, forkhead box O1; IL−6, interleukin−6; IL−10, interleukin−10; NF–κB p65, nuclear factor kappa–B p65 subunit; p–Akt, phosphorylated protein kinase B; PPARγ, peroxisome proliferator–activated receptor gamma; SREBP−1, sterol regulatory element–binding protein 1; TGF–β1, transforming growth factor beta 1; TNF–α, tumor necrosis factor–alpha. Signaling pathway components (EGR1/NEDD9/FAK/AKT): early growth response 1, neural precursor cell expressed developmentally down–regulated 9, focal adhesion kinase, protein kinase B.
Gene symbols (italicized) indicate mouse transcripts.
Symbols: ↓, significant decrease; ↑, significant increase.
Clinical studies corroborate these experimental findings. L-carnitine supplementation improves serum lipid parameters—including total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) —in NASH patients (–). High-dose carnitine orotate complex (Godex®) intervention for 6 months significantly decreased controlled attenuation parameter (CAP) values in NAFLD patients, indicating reduced hepatic steatosis (39). Body composition analyses reveal that L-carnitine treatment reduces fat mass, body weight, and body mass index (BMI) in NASH patients (40). Importantly, a randomized controlled trial demonstrated that L-carnitine supplementation reduces the intramyocellular-to-extramyocellular lipid ratio in NAFLD patients, suggesting enhanced clearance and utilization of intracellular lipid stores in skeletal muscle independent of weight changes (41).
Molecular regulation of fatty acid β-oxidation extends beyond core enzymatic machinery (CPT1, CPT2) to include sophisticated transcriptional and post-translational control mechanisms involving AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor α (PPARα), and peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) (, 42–44). Multiple lines of evidence indicate that L-carnitine supplementation modulates these regulatory networks in NAFLD/NASH models. Sunagozaka et al. (45) reported increased Pparα gene expression in NASH mice after L-carnitine treatment, while Ishikawa et al. (46) observed concurrent upregulation of Pparα and Pparγ. Mollica et al. (47) demonstrated elevated Pparγ protein levels in NAFLD mice receiving L-carnitine.
AMPK serves as a central energy sensor regulating hepatic fatty acid metabolism. During fasting, AMPK activation stimulates sirtuin 1 (SIRT1), which deacetylates and activates transcriptional coactivator PGC1α (48, 49). SIRT1 also enhances PPARα transcriptional activity (50), while PGC1α functions as a PPARα coactivator to promote β-oxidation (51). Basic research indicates that both PPARα and PGC1α stimulate CPT1A transcription by binding distinct regulatory regions within the CPT1A promoter (52). Jun et al. (51) confirmed that L-carnitine increases CPT1A and PPARγ mRNA expression in NAFLD rats. In 2021, Hong et al. () demonstrated that carnitine orotate complex treatment significantly enhances AMPK activation while upregulating Sirt1, Pgc1α, Pparα, Ucp2, and Cpt1 expression in the livers of high-fat diet-fed mice with hepatic steatosis. Complementary in vitro evidence from Montesano et al. (43) shows that L-carnitine reverses fructose-induced AMPK inhibition, increases PGC1α protein levels, reduces reactive oxygen species (ROS) production, and enhances antioxidant factor expression in HepG2 cells. Collectively, these findings suggest that L-carnitine promotes β-oxidation, reduces hepatic lipid accumulation, and exerts antioxidant effects, potentially through the AMPK-SIRT1-PPAR-PGC1α-CPT1 signaling network. Evidence for each component of this network comes from separate preclinical studies, and the precise mechanisms in human MASLD remain to be fully elucidated.
L-carnitine also modulates hepatic lipogenesis through sterol regulatory element-binding protein 1 (SREBP1) regulation. In HFD-fed KK-Ay mice, L-carnitine administration inhibited Srebp1c mRNA overexpression while increasing β-hydroxybutyrate levels, suggesting concurrent lipogenesis suppression and β-oxidation activation (). Hong et al. () provided mechanistic depth by demonstrating that carnitine orotate complex increases carnitine acetyltransferase (CrAT) and β-oxidation-related proteins (CPT1, PPARα, UCP2) while inhibiting SREBP1c nuclear translocation and downstream target gene expression (Hmgcr, Srebp2, Pcsk9, Ldlr) in HFD-fed mice. Crucially, Crat knockout experiments partially reversed these metabolic improvements, establishing CrAT-mediated SREBP1c inhibition as a key mechanism through which L-carnitine counteracts de novo lipogenesis. In summary, L-carnitine appears to balance hepatic lipid metabolism by simultaneously promoting β-oxidation and inhibiting lipogenesis, though detailed SREBP1-related pathway mechanisms warrant further investigation.
At the translational clinical level, L-carnitine primarily targets hepatic steatosis—the earliest pathological step in MASLD. Evidence indicates that supplementation (typically 2–4 g/day) significantly reduces liver fat content and improves systemic lipid profiles. Future translational research should aim to define the “carnitine-responsive” phenotype using integrated approaches, including serum acylcarnitine profiling, quantitative MRI of muscle fat, and CPT1A genotyping to enable precise patient stratification. Building on this, its role as a “metabolic booster” alongside lifestyle interventions, or sequentially with GLP-1 receptor agonists to prevent hepatic fat re-accumulation, warrants further investigation. Additionally, developing novel efficacy endpoints beyond conventional CAP, such as evaluating the specific modulation of hepatic triglyceride composition—particularly the proportion of lipotoxic saturated fatty acids—may more directly elucidate the mechanisms underlying its hepatoprotective effects.
3.2 L-carnitine promotes glucose metabolism and improves insulin resistance
Insulin resistance (IR) represents a fundamental pathogenic mechanism in MASLD, operating throughout the disease spectrum from simple steatosis to MASH and progressive liver fibrosis. L-carnitine's potential to modulate impaired glucose metabolism in MASLD has attracted increasing investigative attention. Clinical evidence demonstrates that L-carnitine supplementation reduces fasting blood glucose (, 39, 53, 54), insulin levels (54, 55), glycated hemoglobin (HbA1c) (56, 57), and ameliorates insulin resistance (, 53, 54) in NAFLD patients. A 2020 meta-analysis of five randomized controlled trials (RCTs) encompassing 334 NAFLD patients confirmed that L-carnitine supplementation significantly improves insulin sensitivity (58). Preclinical studies generally support these clinical observations. NASH model mice treated with L-carnitine exhibited significant improvements in hyperglycemia and hyperinsulinemia (, 59). Godex® markedly reduced fasting blood glucose and insulin resistance indices while enhancing insulin sensitivity in NAFLD mice (). However, not all interventions proved effective, as acetyl-L-carnitine plus alpha-lipoic acid failed to reverse insulin resistance in another NAFLD mouse model (). Overall, L-carnitine may improve insulin resistance in MASLD, with effects influenced by formulation, dosage, treatment length, and experimental model.
Mechanistic insights into L-carnitine's effects on insulin resistance include:
Inhibition of NF-κB-mediated chronic inflammation: NF-κB signaling promotes systemic inflammation and directly interferes with insulin signaling pathways, exacerbating IR (60). L-carnitine suppressed NF-κB expression and downregulated key inflammatory mediators, including NLRP3 inflammasome, Toll-like receptor 4 (TLR4), and c-Jun N-terminal kinase (JNK) ().
Synergistic upregulation of energy metabolism and insulin signaling genes: Salic et al. (61) demonstrated that combined L-carnitine and nicotinamide riboside administration upregulated multiple metabolic and insulin signaling regulators (Ppargc1b, Acox1), promoting mitochondrial oxidative phosphorylation and peripheral glucose uptake.
In vitro evidence suggests that L-carnitine may modulate insulin-like signaling pathways in hepatocytes, including IGF1-associated AKT and p70 S6 kinase signaling; however, this observation is primarily supported by conference-level data and requires further validation (62, 63).
While these findings provide mechanistic plausibility for L-carnitine's effects on IR, most evidence derives from animal or cellular models, with limited human histological validation or pathway-intervention studies. Future multicenter, large-sample RCTs incorporating liver transcriptomics and metabolomics are warranted to optimize dosing and treatment duration in MASLD patients with IR.
The clinical significance of L-carnitine in ameliorating insulin resistance (IR) lies in its intervention in a core pathogenic feature of MASLD: hepatic IR. Meta-analyses of randomized controlled trials indicate that supplementation significantly improves insulin sensitivity, as reflected by reduced HOMA-IR. Future translational efforts should pursue several directions: first, conducting deep-phenotyping trials in biopsy-confirmed MASH patients, using positron emission tomography to quantify hepatic glucose uptake and correlating these findings with intrahepatic insulin signaling (e.g., p-AKT). Second, positioning L-carnitine as a “metabolic re-sensitizer” to evaluate its potential, alone or combined with SGLT2 inhibitors, in restoring hepatic insulin sensitivity among type 2 diabetes patients with MASLD who respond poorly to or cannot tolerate metformin. Finally, delineating tissue-preferential effects is essential to determine whether improvements in IR arise primarily from reduced hepatic lipid content or also involve amelioration of pancreatic steatosis and skeletal muscle lipid metabolism.
4 Regulatory mechanisms of L-carnitine on hepatocyte function
Clinical evidence indicates that L-carnitine improves liver function in NAFLD patients, reflected by reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (, 63). L-carnitine-containing compounds demonstrate comparable hepatoprotective effects. One RCT reported that L-carnitine co-administered with magnesium hydroxide significantly reduced serum AST and ALT (64), while another study found combined L-carnitine and resistance training superior to either intervention alone for liver enzyme reduction (65). In diabetic NAFLD populations, Godex® treatment for 12 weeks significantly improved liver enzymes (56), and L-carnitine monotherapy for 3 months similarly enhanced hepatic function in type 2 diabetes patients with NAFLD (66). Notably, a 2014 randomized double-blind study by Hong et al. demonstrated that adding carnitine orotate complex (900 mg/day, 12 weeks) to metformin therapy significantly augmented ALT reduction versus metformin alone (67). However, the therapeutic response may not be uniform across all patient populations. Age may influence therapeutic efficacy, as a meta-analysis by Liu et al. () found no significant liver enzyme improvement in pediatric patients, primarily based on a single pediatric study that itself showed no clear benefit (68). Mitochondrial dysfunction and oxidative stress constitute central mechanisms in MASH pathogenesis, with MASLD progression closely linked to mitochondrial impairment (69). Consequently, mitochondrial restoration represents a promising therapeutic target in MASLD (70, 71). L-carnitine exerts hepatoprotective effects primarily through mitochondrial mechanisms. Clinical observations by Hong et al. revealed that L-carnitine supplementation increased peripheral blood mitochondrial DNA (mtDNA) copy number while decreasing urinary 8-hydroxy2'-deoxyguanosine (8-OHdG) levels (67), providing clinical evidence of improved mitochondrial function and reduced oxidative stress. Basic research supports this mechanism, demonstrating that fructose or HFD exposure induces mitochondrial structural abnormalities, mtDNA depletion, and ATP deficiency, ultimately impairing β-oxidation and hepatocyte function. L-carnitine supplementation mitigated these mitochondrial alterations, restored mtDNA levels, and enhanced β-oxidation capacity (, , 43, 72, 73).
Human studies further corroborate these findings. In NAFLD patients, Godex® supplementation significantly reduced ALT and AST, increased mtDNA copy number, and decreased oxidative stress marker 8-oxo-7, 8-dihydro2'-deoxyguanosine (8-oxo-dG) (74). Analysis of 14 paired liver biopsies revealed significantly lower baseline peripheral mtDNA copy number in NASH versus simple steatosis patients, establishing an association between mitochondrial dysfunction and disease severity.
L-carnitine also ameliorates oxidative stress by reducing ROS production (43, 47, 75), decreasing hepatic malondialdehyde (MDA) content (, 59, 76), lowering 8-OHdG concentrations, and attenuating 4-hydroxynonenal (4-HNE) immunostaining intensity (45). Concurrently, it enhances antioxidant defenses through SOD2 and nuclear factor erythroid 2-related factor 2 (Nrf2) upregulation (43), ameliorating hepatic inflammation in NAFLD models. Furthermore, L-carnitine upregulates genes involved in fatty acid transport and mitochondrial β-oxidation (Octn2, Cpt1a, Cpt2, Acadm) while increasing metabolites associated with TCA cycle, urea cycle, and antioxidant pathways (malate, citrulline) (45). These coordinated effects collectively promote hepatic metabolic homeostasis restoration.
Beyond mitochondrial mechanisms, L-carnitine inhibits hepatocyte autophagy and apoptosis. In HepG2 cells, L-carnitine reduced free fatty acid-induced apoptosis (72), while similar anti-apoptotic effects occurred in oleic acid-treated hepatocytes (77). A 2024 study in dexamethasone-induced NASH rats demonstrated that L-carnitine restored Akt phosphorylation, inhibited FOXO1 nuclear translocation, and downregulated autophagy and apoptosis markers (LC3, P62, caspase-3, p-MLKL) via the Akt/FOXO1 pathway (59). In summary, L-carnitine improves MASLD through multiple mechanisms including mitochondrial protection, oxidative stress reduction, and autophagy/apoptosis suppression. While current research focuses predominantly on hepatocytes, potential Kupffer cell modulation in NASH-related inflammation and fibrosis warrants further investigation (78).
The hepatoprotective properties of L-carnitine confer clinical value beyond mere transaminase reduction, potentially delaying disease progression by stabilizing mitochondrial function. Clinically observed concomitant decreases in serum ALT/AST and increases in peripheral blood mitochondrial DNA copy number highlight its in vivo bioactivity. To advance translational applications, future studies should focus on: (1) transforming dynamic biomarkers into clinical decision-making tools, such as evaluating early changes in circulating mitochondrial-derived vesicles or oxidative stress markers (e.g., 8–iso–prostaglandin F2α (8-iso-PGF2α))to predict subsequent biochemical and histological responses; (2) developing combination therapies for specific pathological subtypes, including potential synergistic benefits with mitochondria-targeted antioxidants (e.g., MitoQ) or bile acid modulators (e.g., ursodeoxycholic acid, UDCA) in MASH patients with prominent ballooning degeneration or cholestatic features; and (3) assessing prophylactic hepatoprotective potential in high-risk MASLD populations, such as patients on concomitant statin therapy, to broaden clinical applicability.
5 Mechanisms of the anti-inflammatory and anti-fibrotic effects of L-carnitine
Preclinical studies consistently demonstrate that L-carnitine ameliorates liver pathology in NAFLD animal models, improving steatosis, lobular inflammation, and fibrosis (, , 45, 47, 72, 73). L-carnitine-containing compounds show comparable efficacy (, , 61, 79, 80). The anti-inflammatory effects involve inflammatory mediator and signaling pathway suppression. NAFLD-associated chronic low-grade inflammation responds to L-carnitine supplementation through reduced hepatic pro-inflammatory cytokines (e.g., IL-6), increased anti-inflammatory cytokine IL-10, and downregulation of key inflammatory pathway components (TLR4, NF-κB, JNK) ().
NF-κB represents a master regulator of inflammatory responses in NAFLD progression. Ligand-activated PPARγ can inhibit NF-κB signaling by impeding p65 nuclear translocation and reducing p65/PPARγ complex formation (81). In methionine-choline deficient (MCD) diet-induced NAFLD mice, L-carnitine upregulated hepatic PPARγ protein expression while inhibiting NF-κB p65 activation, thereby attenuating liver inflammation and fibrosis (47). Similarly, in HFD-induced obese rats, L-carnitine reduced TNF-α and TGF-β1 protein levels, further mitigating inflammatory responses (). Cellular studies confirm TNF-α, TGF-β1, and procollagen type I mRNA downregulation following L-carnitine treatment (77).
Clinical evidence supports these anti-inflammatory effects. Malaguarnera (), Amiri-Moghadam (82), and Zvyagintseva et al. () reported reduced serum CRP, TNF-α, and IL-6 levels in NASH patients after L-carnitine intervention. The randomized controlled trial by Malaguarnera et al. showed that 24-week L-carnitine treatment improved liver histology, including reduced lobular inflammation, portal inflammation, and fibrosis (). A 2024 study in MASH patients and mouse models further confirmed that L-carnitine supplementation suppresses inflammatory gene expression (Tnf, Il6, Il1b) and downregulates pro-fibrotic genes (Acta2, Col1a2, Tgfb1, Pdgfrb, Pdgf-b, Pdgf-c), reducing α-smooth muscle actin (α-SMA) and platelet-derived growth factor receptor beta (PDGFRβ) protein levels (73). Collectively, these preclinical and clinical findings indicate that L-carnitine can delay MASLD progression by mitigating hepatic inflammation and fibrosis through multiple interconnected mechanisms.
The anti-inflammatory and anti-fibrotic properties of L-carnitine underscore its potential to halt MASLD progression to advanced stages. Key randomized controlled trials have demonstrated its efficacy in improving histologic measures of hepatic inflammation and fibrosis. Future translational strategies should prioritize two directions. First, identifying and targeting patients with an “active inflammatory-fibrotic” phenotype, typically characterized by elevated baseline IL-6 or high-sensitivity C-reactive protein, or by MRI-PDFF-evidenced steatosis with elevated T1 mapping values. Second, evaluating L-carnitine as a “background therapy” in combination with novel anti-fibrotic agents (e.g., GLP-1/GIP dual receptor agonists, FGF21 analogs) to assess its role in consolidating therapeutic efficacy and reducing relapse risk after drug discontinuation.
6 Tumor-suppressive properties of L-carnitine
Overall, preclinical evidence suggests that L-carnitine may contribute to hepatoprotection, although robust clinical evidence for anti-tumor efficacy in humans is currently lacking. In a novel NASH mouse model, low carnitine levels combined with impaired glucose tolerance were associated with enhanced hepatocarcinogenesis (83). Neural precursor cell expressed, developmentally down–regulated 9 (NEDD9), a scaffolding protein associated with poor prognosis in multiple cancers, shows significantly elevated expression in hepatocellular carcinoma (HCC) tissues versus adjacent non-tumor liver (84). Lyu et al. (73) reported that in hepatocytes, L-carnitine inhibited stress-induced transcription factor early growth response protein 1 (EGR1), subsequently downregulating its target gene NEDD9 and modulating the NEDD9/FAK/AKT pathway, signaling pathway, indicating a potential protective mechanism in that experimental context.
Furthermore, L-carnitine may function as an endogenous HDAC inhibitor, promoting p21∧Cip1 expression. Huang et al. demonstrated that in HepG2 cells, L-carnitine acts as an endogenous histone deacetylase inhibitor, promoting p21∧Cip1 expression (85). This epigenetic regulation may represent another avenue for hepatoprotective effects; however, its relevance in human MASLD or metabolic HCC remains to be established.
In addition, a rat hepatitis-HCC model suggested that L-carnitine might mitigate processes associated with hepatocarcinogenesis, such as oxidative stress, and improve mitochondrial function (75). Given that chronic hepatitis and cirrhosis are major risk factors for HCC, the anti-inflammatory and anti-fibrotic effects of L-carnitine could theoretically contribute to reduced HCC risk in patients with advanced MASLD, but this hypothesis awaits clinical validation.
The potential tumor-suppressive effects of L-carnitine provide a unique chemopreventive perspective for long-term MASLD management. Although direct clinical evidence for anti-HCC activity in humans is lacking, its ability to attenuate insulin resistance, oxidative stress, and the inflammation-fibrosis cascade may indirectly reduce HCC risk by optimizing the hepatic oncogenic microenvironment. Future research should employ pragmatic and innovative strategies: first, leveraging real-world data through nested case-control studies linking dietary supplement usage with cancer registries to generate preliminary epidemiological insights into the association between long-term L-carnitine use and HCC incidence in MASLD populations; second, focusing on high-risk cohorts, such as patients with MASH-related compensated cirrhosis, using dynamic contrast-enhanced ultrasound (DCE-US) to monitor de novo nodule emergence and evolution (e.g., arterial phase hyperenhancement) as surrogate endpoints for preliminary chemopreventive assessment; and third, exploring potential synergy with existing HCC surveillance by investigating whether L-carnitine supplementation enhances the sensitivity of serum biomarkers such as protein induced by vitamin K absence-II (PIVKA-II) or alpha-fetoprotein L3 (AFP-L3) for early detection.
7 Discussion
Current MASLD management primarily relies on lifestyle interventions, including weight reduction, dietary modification, and physical activity (86, 87). However, effective pharmacotherapeutic options remain limited. The 2024 FDA approval of resmetirom, the first targeted therapy for MASLD/MASH, represents a significant advancement (88). As a thyroid hormone receptor β agonist, resmetirom improves hepatic steatosis, inflammation, and fibrosis while providing lipid and cardiovascular benefits. Nevertheless, interindividual response variability, high cost, and adherence challenges may limit widespread clinical implementation.
This review has systematically summarized evidence suggesting that L-carnitine exerts multi-targeted actions against MASLD pathogenesis by promoting lipid metabolism, improving insulin sensitivity, stabilizing hepatocyte function, and inhibiting inflammatory and fibrotic signaling pathways. As a dietary supplement, L-carnitine offers advantages including favorable safety profile, convenient administration, and potential efficacy, positioning it as a promising adjunctive option for MASLD management. Available clinical evidence regarding L-carnitine supplementation in MASLD is summarized in Table 2, highlighting both reported metabolic benefits and the current limitations and heterogeneity of human studies. Several important questions remain unresolved, including dosing regimen standardization, limited robust clinical evidence, and insufficient carnitine derivative investigation. Notably, the enantiomer D-carnitine may exert hepatotoxic effects (89), underscoring the critical importance of compound-specific safety evaluation and reinforcing that only the biologically active L-isomer should be considered for therapeutic use in MASLD.
Table 2
| Reference | Disease | Sample size | Duration | Dose | Outcomes |
|---|---|---|---|---|---|
| Hamza et al. (53) | NAFLD | 100 (50/50) | 24 weeks | 50 mg/kg/day | ↓ Chemerin, BMI, WC, HC, WHR, ALT, AST, FPG, HOMA-IR, NAFLD severity ↑ Glucose/insulin ratio → TC, TG, LDL, HDL |
| Lyu et al. (73) | MASH | 11 | 10 weeks | 2,000 mg/day | ↓ ALT, AST, GGT, TG ↓ NAS, inflammation, ballooning ↑ Oxidative stress repair (PRDX2) and lipid metabolism genes (PPARA, CPT1A) ↓ Inflammation (CCL21), fibrosis (COL1A1, COL1A2) genes → TC, FBG, HbA1c; hepatic steatosis grade, fibrosis stage |
| Malaguarnera et al. () | NASH | 74 (36/38) | 24 weeks | 2,000 mg/day | ↓ AST, ALT, GGT, TC, LDL-C, TG, FPG, HOMA-IR, CRP, TNF-α ↑ HDL-C ↓ steatosis, inflammation, ballooning, and fibrosis |
| Somi et al. (63) | NAFLD | 80 (40/40) | 24 weeks | 500 mg/day | ↓ AST, ALT, BMI, Weight, Sonographic grade within-group |
| Thiagarajan et al. (41) | NAFLD | 18 (9/9) | 24 weeks | 4,000 mg/day | ↓ ALT, IHTG, Muscle Lipid Fractions → M, Adipo-IR, body weight |
| Mohammadi et al. (65) | NAFLD | 40 (10/group) | 12 weeks | 10 mg/kg/day | ↓ AST, ALT, BMI, PBF in exercise and combined groups → BMI or PBF with L-carnitine supplementation alone |
| Alavinejad et al. (66) | NAFLD + Diabetes | 60 (30/group) | 3 months | 750 mg/day | ↓ AST, ALT → TC, TG, FBS, sonographic degree of fatty liver. |
Human studies on L-carnitine supplementation in MASLD.
MASLD, metabolic dysfunction–associated steatotic liver disease; NAFLD, non–alcoholic fatty liver disease; NASH, non–alcoholic steatohepatitis; MASH, metabolic dysfunction–associated steatohepatitis.
Clinical and metabolic parameters: Adipo–IR, adipose tissue insulin resistance index; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CRP, C–reactive protein; FBG, fasting blood glucose; FPG, fasting plasma glucose; GGT, γ-glutamyl transferase; HbA1c, glycated hemoglobin; HC, hip circumference; HDL, high–density lipoprotein; HOMA–IR, homeostatic model assessment of insulin resistance; IHTG, intrahepatic triglyceride content; LDL, low–density lipoprotein; M, whole–body insulin sensitivity (hyperinsulinemic–euglycemic clamp); NAS, NAFLD activity score; PBF, percentage of body fat; TC, total cholesterol; TG, triglycerides; WC, waist circumference; WHR, waist–to–hip ratio.
Gene symbols (italicized) indicate human transcripts (e.g., PRDX2, PPARA).
Symbols: ↓, significant decrease; ↑, significant increase; → , no significant change.
Recent research has illuminated the gut-liver axis in MASLD pathogenesis (90, 91). One study reported that a metabolic cofactor combination (L-carnitine, betaine, N-acetylcysteine, nicotinamide riboside) improved intestinal architecture, reduced permeability, and restored tight junction protein expression in NAFLD mice, thereby enhancing gut barrier function (92). Gut inflammasome activation shows close NAFLD association (93), and combined L-carnitine and vitamin E supplementation upregulated gut inflammasome-related genes while ameliorating liver inflammation and fibrosis in a NASH mouse model (94). These findings suggest that gut-liver axis modulation may contribute to L-carnitine's mechanisms of action, although the precise molecular mechanisms remain to be elucidated.
Animal model metabolomics studies reveal that HFD-induced NAFLD is characterized by hepatic saturated fatty acid (myristic acid, palmitic acid) and monounsaturated fatty acid (oleic acid) accumulation, accompanied by decreased gluconeogenic amino acid (glycine, alanine, aspartic acid, glutamic acid, proline) levels (95). However, the specific role of carnitine, a key molecule involved in lipid metabolism, in these metabolic alterations remains inadequately explored.
Optimal L-carnitine dosing requires further clarification. An early meta-analysis suggested that 3 g/day may be necessary to normalize serum ALT in a significant patient proportion (96), while other studies report benefits with 2 g/day on AST, ALT, and HOMA-IR (). Bae et al. (56) demonstrated that Godex® at 900 mg/day improved AST, ALT, and HbA1c in diabetic NAFLD patients. These variable effective doses highlight the need for systematic dose-response studies to establish optimal dosing regimens.
Beyond dose optimization, combining L-carnitine with nutrients or drugs may synergistically enhance its multi-target metabolic effects by regulating mitochondrial function, fatty acid oxidation, and insulin signaling. For example, co-administration of L-carnitine and α-lipoic acid did not improve insulin resistance but markedly ameliorated mitochondrial ultrastructure and reduced serum liver enzyme levels, suggesting a preferential correction of mitochondrial injury (). In Ldlr−/−Leiden mice, only the combined intervention with nicotinamide riboside, rather than either monotherapy, significantly attenuated obesity and hepatic steatosis, accompanied by coordinated upregulation of genes involved in fatty acid oxidation and insulin signaling (61). Mechanistically, the metabolic benefits of Godex® depend on enhanced activity of CrAT, which modulates mitochondrial acetyl-CoA metabolism and thereby improves insulin sensitivity and hepatic lipid homeostasis (). However, these combination effects are highly dependent on experimental models and co-administered components: synergistic metabolic improvements have been observed in animal studies (80), whereas some human studies report only modest reductions in liver enzymes without significant changes in broader metabolic parameters (64). Clinically, accumulating evidence indicates that combinations of L-carnitine with vitamin E, silymarin, or simvastatin can improve liver function and selected metabolic indices (, 54, 55). Overall, the therapeutic potential of L-carnitine–based combination strategies is most likely to be maximized when they are tailored to specific pathological contexts and concurrently target key processes such as fatty acid oxidation, insulin signaling, oxidative stress, and gut barrier integrity (92). These findings highlight the potential of combination strategies to maximize metabolic benefits, warranting further investigation in clinical studies.
Building on these findings, the clinical evidence collated in Table 2 reveals substantial heterogeneity in the therapeutic efficacy of L-carnitine supplementation for MASLD. Although certain trials demonstrate benefits in insulin sensitivity and hepatic steatosis, others report neutral outcomes. This discrepancy primarily stems from methodological variations in patient selection, intervention design, and endpoint assessment, rather than contradicting the established biological plausibility of LC's mechanisms. Patient phenotype critically defines the responsive subset. Individuals with active MASH—marked by significant mitochondrial dysfunction and inflammatory activity—represent a more susceptible population. Here, LC, functioning as an essential cofactor and metabolic regulator, directly counteracts core pathological processes by enhancing mitochondrial β-oxidation and attenuating oxidative stress. In contrast, patients with early-stage steatosis or those embedded in a context of profound systemic insulin resistance may present a less amenable target for short-term LC monotherapy, as the driving pathophysiology extends beyond immediate fatty acid flux. Pharmacological determinants—dose and duration—govern target engagement. Higher doses (≥2000 mg/day) likely saturate hepatic OCTN2 transporters and elevate intracellular carnitine sufficiently to activate CPT1-mediated fatty acid oxidation. Intervention duration influences the cumulative process from molecular adaptations to tissue-level pathological improvements. Quantitative endpoints, such as MRI-PDFF and histology, can capture subtle yet clinically meaningful changes, whereas ALT/AST and ultrasonography may miss early metabolic improvements. Together, these findings underscore that LC's variable clinical efficacy arises from interacting factors including patient phenotype, dosing strategy, intervention duration, and endpoint sensitivity.
In conclusion, MASLD pathogenesis involves complex interactions among multiple metabolic pathways, including dysregulated lipid metabolism, insulin resistance, inflammation, and oxidative stress. L-carnitine, as a key cofactor in fatty acid transport and energy metabolism, exerts multifaceted effects that may modulate these pathogenic processes. While preclinical studies provide promising evidence, clinical validation remains limited across disease stages. Future research should focus on elucidating L-carnitine's molecular mechanisms within the hepatic metabolic network and rigorously assessing its safety and efficacy in well-designed clinical trials. Such efforts hold the potential to advance novel prevention and therapeutic strategies for MASLD.
Previous reviews have summarized the biological functions and therapeutic potential of L-carnitine primarily within the traditional NAFLD/NASH framework (97, 98), but they have not systematically reassessed its relevance under the updated diagnostic criteria and conceptual transition to MASLD. Moreover, emerging mechanistic and clinical evidence published in recent years has not yet been comprehensively integrated. To address these gaps and advance the field, the present review provides several distinct contributions. First, we adopt the latest MASLD/MASH nomenclature to align our discussion with current international consensus. Second, we integrate recent molecular evidence spanning both classical and emerging pathways in lipid metabolism (including AMPK, SIRT1, PPARα, and PGC1α) as well as metabolic–inflammatory signaling related to insulin resistance (e.g., activation of IGF-1/AKT and inhibition of NF-κB). We also summarize newly proposed mechanisms associated with hepatoprotection and tumor suppression, such as attenuation of hepatocellular stress through inhibition of the NEDD9/FAK/AKT cascade and a potential role in cell-cycle regulation via the HDAC/p21 axis—although the latter remains to be validated in MASLD-specific models. Third, we synthesize key preclinical studies and randomized controlled trials published in the last 10 years to provide a timely and critical appraisal of efficacy and safety. Finally, we highlight major limitations in the current evidence—such as heterogeneous dosing regimens, the scarcity of long-term clinical data, and insufficient mechanistic validation under MASLD conditions—and propose directions for future translational research.
Statements
Author contributions
CC: Writing – original draft, Writing – review & editing. JZ: Conceptualization, Project administration, Supervision, Writing – review & editing. LL: Investigation, Writing – review & editing. SL: Investigation, Visualization, Writing – review & editing. ZL: Investigation, Writing – review & editing. LY: Investigation, Writing – review & editing. PP: Investigation, Writing – review & editing. JL: Investigation, Writing – review & editing. ZC: Investigation, Writing – review & editing. HH: Investigation, Writing – review & editing. JH: Conceptualization, Supervision, Writing – review & editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Acknowledgments
The authors gratefully acknowledge the contributions of researchers in the field of MASLD and carnitine metabolism, whose foundational work has informed this study. The figure was created using Adobe Illustrator.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1.
YounossiZMGolabiPPaikJMHenryAVan DongenCHenryL. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. (2023) 77:1335–47. doi: 10.1097/HEP.0000000000000004
2.
SinghSAllenAMWangZProkopLJMuradMHLoombaR. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. (2015) 13:643-54.e1-9; quiz e39-40. doi: 10.1016/j.cgh.2014.04.014
3.
KalligerosMHenryLYounossiZM. Metabolic dysfunction-associated steatotic liver disease and its link to cancer. Metabolism. (2024) 160:156004. doi: 10.1016/j.metabol.2024.156004
4.
BallestriSZonaSTargherGRomagnoliDBaldelliENascimbeniF. et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. (2016) 31:936–44. doi: 10.1111/jgh.13264
5.
AbosheaishaaHHusseinMGhallabMAbdelhamidMBalassianoNAhammedMR. et al. Association between non-alcoholic fatty liver disease and coronary artery disease outcomes: A systematic review and meta-analysis Diabetes. Metab Syndr. (2024) 18:102938. doi: 10.1016/j.dsx.2023.102938
6.
MantovaniAPetraccaGBeatriceGCsermelyALonardoASchattenbergJM. et al. Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis. Gut. (2022) 71:156–62. doi: 10.1136/gutjnl-2020-323082
7.
RinellaMELazarusJVRatziuVFrancqueSMSanyalAJKanwalF. et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. (2023) 79:1542–56. doi: 10.1097/HEP.0000000000000696
8.
SongSJLaiJCWongGLWongVWYipTC. Can we use old NAFLD data under the new MASLD definition?J Hepatol. (2024) 80:e54–e6. doi: 10.1016/j.jhep.2023.07.021
9.
RatziuVBoursierJ. Confirmatory biomarker diagnostic studies are not needed when transitioning from NAFLD to MASLD. J Hepatol. (2024) 80:e51–e2. doi: 10.1016/j.jhep.2023.07.017
10.
HagströmHVessbyJEkstedtMShangY. 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. J Hepatol. (2024) 80:e76–e7. doi: 10.1016/j.jhep.2023.08.026
11.
DemarquoyJGeorgesBRigaultCRoyerMCClairetASotyM. et al. Radioisotopic determination of L-carnitine content in foods commonly eaten in Western countries. Food Chem. (2004) 86:137–42. doi: 10.1016/j.foodchem.2003.09.023
12.
SteiberAKernerJHoppelCL. Carnitine: a nutritional, biosynthetic, and functional perspective. Mol Aspects Med. (2004) 25:455–73. doi: 10.1016/j.mam.2004.06.006
13.
PekalaJPatkowska-SokołaBBodkowskiRJamrozDNowakowskiPLochyńskiS. et al. L-carnitine–metabolic functions and meaning in humans life. Curr Drug Metab. (2011) 12:667–78. doi: 10.2174/138920011796504536
14.
VazFMWandersRJ. Carnitine biosynthesis in mammals. Biochem J. (2002) 361:417–29. doi: 10.1042/bj3610417
15.
LongoNAmat di San FilippoCPasqualiM. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet. (2006) 142c:77-85. doi: 10.1002/ajmg.c.30087
16.
CederbaumSDKoo-McCoySTeinIHsuBYGangulyAVilainE. et al. Carnitine membrane transporter deficiency: a long-term follow up and OCTN2 mutation in the first documented case of primary carnitine deficiency. Mol Genet Metab. (2002) 77:195–201. doi: 10.1016/S1096-7192(02)00169-5
17.
CrefcoeurLLVisserGFerdinandusseSWijburgFALangeveldMSjoukeB. Clinical characteristics of primary carnitine deficiency: a structured review using a case-by-case approach. J Inherit Metab Dis. (2022) 45:386–405. doi: 10.1002/jimd.12475
18.
LancasterCSHuCFrankeRMFilipskiKKOrwickSJChenZ. et al. Cisplatin-induced downregulation of OCTN2 affects carnitine wasting. Clin Cancer Res. (2010) 16:4789–99. doi: 10.1158/1078-0432.CCR-10-1239
19.
LiPWangYLuoJZengQWangMBaiM. et al. Downregulation of OCTN2 by cytokines plays an important role in the progression of inflammatory bowel disease. Biochem Pharmacol. (2020) 178:114115. doi: 10.1016/j.bcp.2020.114115
20.
Opden. Kamp-Bruls YMH, Op den Kamp YJM, Veeraiah P, Zapata Perez R, Phielix E, Havekes B, et al. Carnitine supplementation improves insulin sensitivity and skeletal muscle acetylcarnitine formation in patients with type 2 diabetes. Diabetes Obes Metab. (2025) 27:2864–77. doi: 10.1111/dom.16298
21.
KeshaniMAlikiaiiBBabaeiZAskariGHeidariZSharmaM. et al. The effects of L-carnitine supplementation on inflammation, oxidative stress, and clinical outcomes in critically Ill patients with sepsis: a randomized, double-blind, controlled trial. Nutr J. (2024) 23:31. doi: 10.1186/s12937-024-00934-4
22.
OmoriYOhtaniTSakataYManoTTakedaYTamakiS. et al. L-Carnitine prevents the development of ventricular fibrosis and heart failure with preserved ejection fraction in hypertensive heart disease. J Hypertens. (2012) 30:1834–44. doi: 10.1097/HJH.0b013e3283569c5a
23.
KernerJHoppelC. Fatty acid import into mitochondria. Biochim Biophys Acta. (2000) 1486:1–17. doi: 10.1016/S1388-1981(00)00044-5
24.
SchönfeldPWojtczakL. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J Lipid Res. (2016) 57:943–54. doi: 10.1194/jlr.R067629
25.
AasMBremerJ. Short-chain fatty acid activation in rat liver. A new assay procedure for the enzymes and studies on their intracellular localization. Biochim Biophys Acta. (1968) 164:157–66. doi: 10.1016/0005-2760(68)90142-2
26.
FrancoAJCastañéHGayaGBRodríguez-TomàsEAndreuJCMariedJJ. Carnitine signature in liver corretales with non-alcoholic fatty liver disease progression. J Hepatol. (2022) 77:S681. doi: 10.1016/S0168-8278(22)01680-4
27.
ZvyagintsevaTDGlushchenkoSV. The effect of L-Carnitine and proinflammatory cytokines in the development of nonalcoholic steatohepatitis. Bangladesh J Med Sci. (2016) 15:62–5. doi: 10.3329/bjms.v15i1.20660
28.
SunCGuoYCongPTianYGaoX. Liver lipidomics analysis revealed the novel ameliorative mechanisms of L-Carnitine on high-fat diet-induced NAFLD Mice. Nutrients. (2023) 15:1359. doi: 10.3390/nu15061359
29.
MaedaHHosomiRFukudaMIkedaYYoshidaMFukunagaK. Dietary Tuna Dark Muscle Protein Attenuates Hepatic Steatosis and Increases Serum High-Density Lipoprotein Cholesterol in Obese Type-2 Diabetic/Obese KK-A(y) Mice. J Food Sci. (2017) 82:1231–8. doi: 10.1111/1750-3841.13711
30.
Abd EldaimMAIbrahimFMOrabiSHHassanAEl SabaghHS. l-Carnitine-induced amelioration of HFD-induced hepatic dysfunction is accompanied by a reduction in hepatic TNF-α and TGF-β1. Biochem Cell Biol. (2018) 96:713–25. doi: 10.1139/bcb-2018-0074
31.
SunagozakaHHondaMYamashitaTOkadaHOishiNShimakamiT. et al. The L-carnitine alleviate hepatic fibrosis in a non-alcoholic steatohepatitis. Hepatology. (2015) 62:872A.
32.
KathirvelEMorganKFrenchSWMorganTR. Acetyl-L-carnitine and lipoic acid improve mitochondrial abnormalities and serum levels of liver enzymes in a mouse model of nonalcoholic fatty liver disease. Nutr Res. (2013) 33:932–41. doi: 10.1016/j.nutres.2013.08.001
33.
HongJHLeeMK. Carnitine Orotate Complex Ameliorates Insulin Resistance and Hepatic Steatosis Through Carnitine Acetyltransferase Pathway. Diabetes Metab J. (2021) 45:933–47. doi: 10.4093/dmj.2020.0223
34.
KangJSLeeWKYoonWKKimNParkSKParkHK. et al. A combination of grape extract, green tea extract and L-carnitine improves high-fat diet-induced obesity, hyperlipidemia and non-alcoholic fatty liver disease in mice. Phytother Res. (2011) 25:1789–95. doi: 10.1002/ptr.3476
35.
FujisawaKTakamiTMatsuzakiAMatsumotoTYamamotoNTeraiS. et al. Evaluation of the effects of L-carnitine on medaka (Oryzias latipes) fatty liver. Sci Rep. (2017) 7:2749. doi: 10.1038/s41598-017-02924-5
36.
LiuACaiYYuanYLiuMZhangZXuY. et al. Efficacy and safety of carnitine supplementation on NAFLD: a systematic review and meta-analysis. Syst Rev. (2023) 12:74. doi: 10.1186/s13643-023-02238-w
37.
MalaguarneraMGarganteMPRussoCAnticTVacanteMMalaguarneraM. et al. L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis–a randomized and controlled clinical trial. Am J Gastroenterol. (2010) 105:1338–45. doi: 10.1038/ajg.2009.719
38.
ZakharovaNLuoCAringazinaRSamusenkovV. The efficacy of L-carnitine in patients with nonalcoholic steatohepatitis and concomitant obesity. Lipids Health Dis. (2023) 22:101. doi: 10.1186/s12944-023-01867-3
39.
SongJJKoKJChoYKParkHMKooHMKimNR. et al. Effectiveness of high-dose carnitine complex treatment in patients with nonalcoholic fatty liver disease: A retrospective, observational study. J Gastroenterol Hepatol. (2018) 33:423.
40.
Amiri-MoghadamSNematyMEghtesadiSKhaliliMMojarradMJazayeriS. et al. Effects of L-carnitine supplementation on body composition in patients with nonalcoholic steatohepatitis (NASH). Curr Top Nutraceutical Res. (2015) 13:71–6. doi: 10.1016/S0261-5614(17)30566-6
41.
ThiagarajanPBawdenSSimpsonLGowlandPGreenhaffPAithalGP. L-carnitine supplementation in non-alcoholic fatty liver disease: Effects on intrahepatic triglyceride, muscle lipid fractions and liver mitochondrial energetics-results from a pilot randomised trial. Hepatology. (2020) 72:1052A−3A. doi: 10.1136/gutjnl-2020-BASL.10
42.
AshmoreTRobertsLDMorashAJKotwicaAOFinnertyJWestJA. et al. Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism. BMC Biol. (2015) 13:110. doi: 10.1186/s12915-015-0221-6
43.
MontesanoASenesiPVacanteFMollicaGBenediniSMariottiM. et al. L-Carnitine counteracts in vitro fructose-induced hepatic steatosis through targeting oxidative stress markers. J Endocrinol Invest. (2020) 43:493–503. doi: 10.1007/s40618-019-01134-2
44.
Stefanovic-RacicMPerdomoGMantellBSSipulaIJBrownNFO'DohertyRMet al. moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels. Am J Physiol Endocrinol Metab. (2008) 294:E969–77. doi: 10.1152/ajpendo.00497.2007
45.
IshikawaHTakakiATsuzakiRYasunakaTKoikeKShimomuraY. et al. L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model with upregulation of mitochondrial pathway. PLoS ONE. (2014) 9:e100627. doi: 10.1371/journal.pone.0100627
46.
IshikawaHTakakiAYamamotoK. L-carnitine prevents progression of non-alcoholic steatohepatitis with regulation of mitochondrial β-oxidation and redox system in NASH model Mice. Hepatology. (2013) 58:561A.
47.
MollicaGSenesiPCodellaRVacanteFMontesanoALuziL. et al. L-carnitine supplementation attenuates NAFLD progression and cardiac dysfunction in a mouse model fed with methionine and choline-deficient diet. Dig Liver Dis. (2020) 52:314–23. doi: 10.1016/j.dld.2019.09.002
48.
RodgersJTLerinCHaasWGygiSPSpiegelmanBMPuigserverP. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. (2005) 434:113–8. doi: 10.1038/nature03354
49.
ZhugeALiSHanSYuanYShenJWuW. et al. Akkermansia muciniphila-derived acetate activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis in metabolic-associated fatty liver disease. Acta Pharm Sin B. (2025) 15:151–67. doi: 10.1016/j.apsb.2024.10.010
50.
PurushothamASchugTTXuQSurapureddiSGuoXLiX. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. (2009) 9:327–38. doi: 10.1016/j.cmet.2009.02.006
51.
VegaRBHussJMKellyDP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. (2000) 20:1868–76. doi: 10.1128/MCB.20.5.1868-1876.2000
52.
SongSAttiaRRConnaughtonSNiesenMINessGCElamMB. et al. Peroxisome proliferator activated receptor alpha (PPARalpha) and PPAR gamma coactivator (PGC-1alpha) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elements. Mol Cell Endocrinol. (2010) 325:54–63. doi: 10.1016/j.mce.2010.05.019
53.
HamzaRTElkabbanyZAShedidAMHamedAIEbrahimAO. Serum chemerin in obese children and adolescents before and after L-Carnitine therapy: relation to nonalcoholic fatty liver disease and other features of metabolic syndrome. Arch Med Res. (2016) 47:541–9. doi: 10.1016/j.arcmed.2016.11.010
54.
PoulosJEKalogerinisPTMilanovVKalogerinisCTPoulosEJ. The Effects of Vitamin E, silymarin and carnitine on the metabolic abnormalities associated with nonalcoholic liver disease. J Diet Suppl. (2022) 19:287–302. doi: 10.1080/19390211.2021.1874587
55.
PoulosJMilanovV. Triple therapy utilizing vitamin E, milk thistle, and carnitine improves ALT and the metabolic abnormalities associated with NAFLD. Diabetes. (2016) 65:A617–A8.
56.
BaeJLeeWYoonKParkJSonHHanK. et al. A multicentric, double-blind, randomised-controlled trial (RCT) of carnitine orotate complex in diabetic patients with non-alcoholic fatty liver disease (NAFLD). Diabetologia. (2014) 57:S349–S50.
57.
BaeJCLeeWYYoonKHParkJYSonHSHanKA. et al. Improvement of Nonalcoholic Fatty Liver Disease With Carnitine-Orotate Complex in Type 2 Diabetes (CORONA): a randomized controlled trial. Diabetes Care. (2015) 38:1245–52. doi: 10.2337/dc14-2852
58.
AbolfathiMMohd-YusofBNHanipahZNMohd RedzwanSYusofLMKhosroshahiMZ. The effects of carnitine supplementation on clinical characteristics of patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. Complement Ther Med. (2020) 48:102273. doi: 10.1016/j.ctim.2019.102273
59.
AmerAEGhoneimHAAbdelazizRRShehatouGSGSuddekGM. L-carnitine attenuates autophagic flux, apoptosis, and necroptosis in rats with dexamethasone-induced non-alcoholic steatohepatitis. BMC Pharmacol Toxicol. (2024) 25:102. doi: 10.1186/s40360-024-00820-z
60.
SajanMPStandaertMLNimalSVaranasiUPastoorTMastoridesS. et al. The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFkappaB in obesity. J Lipid Res. (2009) 50:1133–45. doi: 10.1194/jlr.M800520-JLR200
61.
SalicKGartESeidelFVerschurenLCaspersMvan DuyvenvoordeWet al. Combined treatment with L-Carnitine and nicotinamide riboside improves hepatic metabolism and attenuates obesity and liver steatosis. Int J Mol Sci. (2019) 20: doi: 10.3390/ijms20184359
62.
TerruzziISenesiPMontesanoAMazzilliMLuziL. Effect of l-carnitine on hepatocyte insulin action and metabolism. Diabetes. (2015) 64:A181.
63.
SomiMHFatahiEPanahiJHavasianMRJudakiA. Data from a randomized and controlled trial of L–Carnitine prescription for the treatment for Non- Alcoholic Fatty Liver Disease. Bioinformation. (2014) 10:575–9. doi: 10.6026/97320630010575
64.
HazzanRAbu AhmadNSlimWMazenENeemanZ. Hepatoprotective effect of combination of L-carnitine and magnesium-hydroxide in nonalcoholic fatty liver disease patients: a double-blinded randomized controlled pilot study. Eur Rev Med Pharmacol Sci. (2022) 26:7522–32. doi: 10.26355/eurrev_202210_30023
65.
MohammadiFGhalavandADelaramnasabM. Effect of circuit resistance training and l-carnitine supplementation on body composition and liver function in men with non-alcoholic fatty liver disease. Jundishapur J Chronic Dis Care. (2019) 8: doi: 10.5812/jjcdc.90213
66.
AlavinejadPZakerkishMEskandarH. Hashemi sJ, Chobineh M, Moghaddam E. Evaluation of L-Carnitine efficacy in the treatment of non- alcoholic fatty liver disease among diabetic patients: a randomized double blind pilot study. J Gastroenterol Hepatol Res. (2016) 5:2191–5. doi: 10.17554/j.issn.2224-3992.2016.05.662
67.
HongESKimEKKangSMKhangARChoiSHParkKS. et al. Effect of carnitine-orotate complex on glucose metabolism and fatty liver: a double-blind, placebo-controlled study. J Gastroenterol Hepatol. (2014) 29:1449–57. doi: 10.1111/jgh.12536
68.
SaneianHKhalilianLHeidari-BeniMKhademianMFamouriFNasriP. et al. Effect of l-carnitine supplementation on children and adolescents with nonalcoholic fatty liver disease (NAFLD): a randomized, triple-blind, placebo-controlled clinical trial. J Pediatr Endocrinol Metab. (2021) 34:897–904. doi: 10.1515/jpem-2020-0642
69.
MuCWangSWangZTanJYinHWangY. et al. Mechanisms and therapeutic targets of mitochondria in the progression of metabolic dysfunction-associated steatotic liver disease. Ann Hepatol. (2025) 30:101774. doi: 10.1016/j.aohep.2024.101774
70.
MengDChangMDaiXKuangQWangG. GTPBP8 mitigates nonalcoholic steatohepatitis (NASH) by depressing hepatic oxidative stress and mitochondrial dysfunction via PGC-1α signaling. Free Radic Biol Med. (2025) 229:312–32. doi: 10.1016/j.freeradbiomed.2024.09.044
71.
ZhangMJiJLeiYQinFTaoYLiN. et al. Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement. Pharmacol Res. (2025) 215:107706. doi: 10.1016/j.phrs.2025.107706
72.
JunDWChoWKJunJHKwonHJJangKSKimHJ. et al. Prevention of free fatty acid-induced hepatic lipotoxicity by carnitine via reversal of mitochondrial dysfunction. Liver Int. (2011) 31:1315–24. doi: 10.1111/j.1478-3231.2011.02602.x
73.
LyuJOkadaHSunagozakaHKawaguchiKShimakamiTNioKet al. Potential utility of l-carnitine for preventing liver tumors derived from metabolic dysfunction-associated steatohepatitis. Hepatol Commun. (2024) 8:e0425. doi: 10.1097/HC9.0000000000000425
74.
LimCYJunDWJangSSChoWKChaeJDJunJH. Effects of carnitine on peripheral blood mitochondrial DNA copy number and liver function in non-alcoholic fatty liver disease. Korean J Gastroenterol. (2010) 55:384–9. doi: 10.4166/kjg.2010.55.6.384
75.
ChangBNishikawaMNishiguchiSInoueM. L-carnitine inhibits hepatocarcinogenesis via protection of mitochondria. Int J Cancer. (2005) 113:719–29. doi: 10.1002/ijc.20636
76.
PradhanyRCSiswantoFMSukocoHNyoman SuarsanaIGusti Ayu Agung SuartiniI. L-carnitine Prevents Hepatic Steatosis in Deep-Frying Oil-Treated Rat. Biomed Pharmacol J. (2022) 15:1751–8. doi: 10.13005/bpj/2514
77.
ZengXShengX. The restorative effect of l-carnitine on experimental nonalcoholic steatohepatitis. Gastroenterology. (2013) 144:S1022. doi: 10.1016/S0016-5085(13)63795-6
78.
YuYLiuYAnWSongJZhangYZhaoX. STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis. J Clin Invest. (2019) 129:546–55. doi: 10.1172/JCI121842
79.
KangJSLeeWKLeeCWYoonWKKimNParkSK. et al. Improvement of high-fat diet-induced obesity by a mixture of red grape extract, soy isoflavone and L-carnitine: implications in cardiovascular and non-alcoholic fatty liver diseases. Food Chem Toxicol. (2011) 49:2453–8. doi: 10.1016/j.fct.2011.06.071
80.
NofalAEAboShabaanHSFaddaWAErebaREElsharkawySMHathoutHM. L-carnitine and Ginkgo biloba Supplementation In Vivo Ameliorates HCD-Induced Steatohepatitis and Dyslipidemia by Regulating Hepatic Metabolism. Cells. (2024) 13:732. doi: 10.3390/cells13090732
81.
FengXWengDZhouFOwenYDQinHZhaoJ. et al. Activation of PPARγ by a Natural Flavonoid Modulator, Apigenin Ameliorates Obesity-Related Inflammation Via Regulation of Macrophage Polarization. EBioMedicine. (2016) 9:61–76. doi: 10.1016/j.ebiom.2016.06.017
82.
EghtesadiSAmiri MoghadamSNematiMKhaliliMMojarradMJazayeriS. et al. Effects of L-carnitine supplementation on inflammatory factors and malondialdehyde in patients with nonalcoholic steatohepatitis (NASH). Obesity Facts. (2016) 9:184.
83.
TerayamaYNakamuraSIMekadaKMatsuuraTOzakiK. High-fat diet-induced nonalcoholic steatohepatitis is accelerated by low carnitine and impaired glucose tolerance in novel murine models. Lab Invest. (2022) 102:621–30. doi: 10.1038/s41374-022-00732-8
84.
MatterMSMarquardtJUAndersenJBQuintavalleCKorokhovNStaufferJK. et al. Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype. Hepatology. (2016) 63:1888–99. doi: 10.1002/hep.28487
85.
HuangHLiuNGuoHLiaoSLiXYangC. et al. L-carnitine is an endogenous HDAC inhibitor selectively inhibiting cancer cell growth in vivo and in vitro. PLoS ONE. (2012) 7:e49062. doi: 10.1371/journal.pone.0049062
86.
RinellaMENeuschwander-TetriBASiddiquiMSAbdelmalekMFCaldwellSBarbD. et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. (2023) 77:1797–835. doi: 10.1097/HEP.0000000000000323
87.
EASL-EASD-EASO. Clinical practice guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). Obes Facts. (2024) 17:374-444. doi: 10.1159/000539371
88.
PettaSTargherGRomeoSPajvaniUBZhengMHAghemoA. et al. The first MASH drug therapy on the horizon: Current perspectives of resmetirom. Liver Int. (2024) 44:1526–36. doi: 10.1111/liv.15930
89.
Li JM LiLYZhangYXJiangZYLimbuSMQiaoF. et al. Functional differences between l- and d-carnitine in metabolic regulation evaluated using a low-carnitine Nile tilapia model. Br J Nutr. (2019) 122:625–38. doi: 10.1017/S000711451900148X
90.
SuXChenSLiuJFengYHanEHaoX. et al. Composition of gut microbiota and non-alcoholic fatty liver disease: a systematic review and meta-analysis. Obes Rev. (2024) 25:e13646. doi: 10.1111/obr.13646
91.
ZhangDLeitmanMPawarSSheraSHernandezLJacobsJPet al. The association between prevotella copri and advanced fibrosis in the progression of metabolic dysfunction-associated steatotic liver disease. Nutrients. (2025) 17:2145. doi: 10.3390/nu17132145
92.
Quesada-VázquezSBoneCSahaSTrigueroIColom-PellicerMAragonèsGet al. Microbiota dysbiosis and gut barrier dysfunction associated with non-alcoholic fatty liver disease are modulated by a specific metabolic cofactors' combination. Int J Mol Sci. (2022) 23:13675. doi: 10.3390/ijms232213675
93.
PierantonelliIRychlickiCAgostinelliLGiordanoDMGagginiMFraumeneC. et al. Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD. Sci Rep. (2017) 7:12200. doi: 10.1038/s41598-017-11744-6
94.
IshikawaH. Vitamin e and l-carnitine prevents progression of non-alcoholic steatohepatitis with regulation of intestinal inflammasome activation in nash model mice. Gastroenterology. (2013) 144:S1019. doi: 10.1016/S0016-5085(13)63782-8
95.
XieZLiHWangKLinJWangQZhaoG. et al. Analysis of transcriptome and metabolome profiles alterations in fatty liver induced by high-fat diet in rat. Metabolism. (2010) 59:554–60. doi: 10.1016/j.metabol.2009.08.022
96.
SochaPHorvathAVajroPDziechciarzPDhawanASzajewskaH. Pharmacological interventions for nonalcoholic fatty liver disease in adults and in children: a systematic review. J Pediatr Gastroenterol Nutr. (2009) 48:587–96. doi: 10.1097/MPG.0b013e31818e04d1
97.
LiNZhaoH. Role of carnitine in non-alcoholic fatty liver disease and other related diseases: an update. Front Med. (2021) 8:689042. doi: 10.3389/fmed.2021.689042
98.
SavicDHodsonLNeubauerSPavlidesM. The Importance of the Fatty Acid Transporter L-Carnitine in Non-Alcoholic Fatty Liver Disease (NAFLD). Nutrients. (2020) 12:2178. doi: 10.3390/nu12082178
Summary
Keywords
insulin resistance, L-carnitine, lipid metabolism, MASLD, mitochondrial function
Citation
Chen C, Zou J, Li L, Liu S, Liu Z, Yao L, Peng P, Liang J, Chen Z, Huang H and Huang J (2026) L–carnitine in metabolic dysfunction-associated steatotic liver disease: mechanisms and therapeutic potential. Front. Nutr. 13:1804917. doi: 10.3389/fnut.2026.1804917
Received
05 February 2026
Revised
04 March 2026
Accepted
16 March 2026
Published
31 March 2026
Volume
13 - 2026
Edited by
Berenice M Román Calleja, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico
Reviewed by
Anindita Banerjee, Indian Council of Medical Research (ICMR), India
Venkateswararao Eeda, University of Oklahoma Health Sciences Center, United States
Updates
Copyright
© 2026 Chen, Zou, Li, Liu, Liu, Yao, Peng, Liang, Chen, Huang and Huang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jun Zou, zoujun8227623@163.com; Jiean Huang, hjagxmu@163.com
† These authors have contributed equally to this work
Disclaimer
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