TO THE EDITOR
The liver, as the largest solid organ in the human body, plays a critical role in various essential functions, including bile secretion, detoxification, immune responses to pathogens, and numerous physiological and metabolic processes[1]. Despite its importance, the liver is vulnerable to damage from factors such as alcohol consumption, drug abuse, overnutrition, and disruptions in the intestinal microbiota. These factors can lead to a range of liver diseases, including alcoholic liver disease (ALD), metabolic-associated fatty liver disease (MAFLD), cholestatic liver disease (CLD), and autoimmune liver disease. These conditions have the potential to progress to more severe outcomes such as cirrhosis and liver cancer[2-4]. Liver diseases considerably affect patients’ quality of life and lead to around 2 million deaths each year, making up about 4% of all fatalities[5]. Current treatment challenges include concerns over drug safety and efficacy, patient adherence, and the need for targeted therapies[6,7]. Effective treatment options are still limited, highlighting the significant potential in discovering safe and reliable drugs for managing these liver diseases.
Elafibranor, a dual agonist of peroxisome proliferator-activated receptor α/δ (PPARα/δ) developed by Genfit, was initially intended for managing hyperlipidemia and type 2 diabetes. Experimental studies suggest that it has potential protective effects on the liver. Currently, Elafibranor is under development for treating MAFLD and primary biliary cholangitis (PBC), positioning it as one of the most promising candidates for treating MAFLD[8-10]. This article explores the prospective applications of Elafibranor in the treatment of a various of liver diseases, drawing from the latest research by Koizumi et al[11].
Evaluation of the study
Annually, over 2 billion people worldwide consume alcohol, with more than 75 million affected by ALD, making it a prevalent liver disorder[12]. ALD progresses through stages including hepatocyte steatosis, alcoholic steatohepatitis, liver fibrosis, and in some cases, cirrhosis[13]. Without intervention, liver fibrosis often progresses to cirrhosis; typically, cirrhosis develops 10 to 20 years after initial fibrosis appears[14]. Cirrhosis is a leading cause of death among individuals with alcohol use disorders[15]. Current therapeutic approaches for ALD predominantly focus on alcohol abstinence. Regrettably, there are no specific pharmacological agents approved to treat ALD-induced liver fibrosis; patients are often managed with symptomatic medications[13]. For individuals with advanced alcoholic cirrhosis or those who do not respond to pharmacological treatment, liver transplantation remains a costly and highly risky option[16,17].
Koizumi et al[11] were pioneers in exploring the protective effects of Elafibranor on the intestinal barrier and hepatic fibrosis induced by ALD. Their research demonstrated that Elafibranor counteracts the reduction in PPARα expression and enhances the expression of PLA2 and COX-2 in hepatic tissue of ALD mice. This indicates that Elafibranor modulates PPARα-mediated lipid metabolism in the liver of ALD models. Further analysis revealed that Elafibranor significantly reduced liver steatosis, necrotic inflammation, and levels of aspartate aminotransferase, alanine aminotransferase, triacylglycerol (TG), and free fatty acids (FAs). Histological examination confirmed these results. Additionally, Elafibranor elevated mRNA levels of markers related to FA oxidation and lipolysis, with no effect on lipid synthesis markers, suggesting that its role is primarily in fat degradation and oxidative metabolism. Elafibranor also influenced antioxidant markers (SOD1 and CAT) and autophagy-related proteins (LC3-II, Atg7, Beclin-1, and p62), thus mitigating hepatocyte apoptosis in the ALD model. Furthermore, Elafibranor effectively inhibited liver fibrosis progression by decreasing α-SMA myofibroblasts, hydroxyproline levels, and matrix metalloproteinase activity, while downregulating fibrosis-associated genes (Acta2, Col1a1, and Tgfb1).
The authors investigated the protective mechanisms of Elafibranor using HepG2 and LX-2 cells and found that Elafibranor primarily activates PPARα. This action reduces hepatocyte apoptosis and lipid accumulation while enhancing autophagy and antioxidant defenses. Elafibranor inhibits hepatic inflammation by blocking macrophage activation through the LPS/TLR4 signaling pathway, thereby preventing NF-κB activation and pro-inflammatory cytokine release. It also boosts tight junction protein expression, preventing intestinal glucan leakage into the portal vein in ALD mouse models. Additionally, Elafibranor reduces intestinal apoptosis due to autophagy dysfunction and shifts macrophage polarization from M1 to M2 types, improving intestinal permeability. By activating PPARδ, Elafibranor restores intestinal epithelial barrier integrity and tight junction protein expression in ethanol-exposed human intestinal cells, while enhancing autophagy-mediated apoptosis. In summary, Elafibranor mitigates hepatic steatosis, apoptosis, fibrosis, and inflammation in ALD models; promotes lipid metabolism, hepatocyte autophagy, and antioxidant capacity through PPARα activation; and protects the intestinal barrier, enhances autophagy, and reduces inflammation via PPARδ activation.
The study comprehensively investigated autophagy, oxidative stress, liver pathology, and cell death in a mouse model of ALD, providing a robust experimental basis for understanding Elafibranor's therapeutic potential in ALD. The results underscore Elafibranor as a potent inhibitor of fatty liver, inflammation, and fibrosis in these mice, suggesting a promising therapeutic strategy for ALD. Moreover, the study highlights Elafibranor's activation of PPARδ to enhance intestinal barrier function, opening new avenues for exploring the etiology and management of ALD.
Nevertheless, several challenges remain. Although mouse models are frequently utilized to study ALD, they do not fully replicate human ALD, necessitating additional validation to confirm the applicability of these findings to human conditions. Furthermore, further research is required to establish the safety and efficacy of Elafibranor in clinical settings, despite its pronounced preventive effects observed in ALD mouse models. While this study has highlighted Elafibranor's influence on intestinal barrier function, a more detailed investigation is needed to elucidate its underlying molecular mechanisms and signaling pathways. Additionally, since the current study utilized a pretreatment approach in the ALD model, future research should assess whether Elafibranor retains its therapeutic efficacy when administered following the onset of ALD.
Although Elafibranor has shown favorable safety profiles in phase I and phase II studies and is currently undergoing phase III clinical trials for metabolic-associated steatohepatitis (MASH) treatment, existing data does not yet support its efficacy in treating liver fibrosis caused by MAFLD[9]. Excessive ethanol consumption can lead to ALD through both direct effects on the liver and indirect effects mediated via the gut. Alcohol abuse exacerbates hepatic fat accumulation, inflammation, and oxidative stress, while also disrupting intestinal barrier function and gut microbiota composition[18]. Further investigation is required to elucidate the specific mechanisms by which Elafibranor may influence liver fibrosis in the contexts of ALD and MAFLD, given their distinct etiologies[13]. Despite these challenges, Elafibranor shows promise for the treatment of liver fibrosis, as evidenced by its amelioration of fibrotic outcomes in an ALD model in this study.
Research progress of Elafibranor in liver diseases
Elafibranor in ALD: Li et al's study investigated the effects of Elafibranor on autophagy dysfunction in a mouse model of ALD[19]. They found that prolonged ethanol consumption led to reduced levels of PPARα and PPARδ, as well as decreased autophagy in the liver, intestine, and adipose tissue of mice. This reduction contributed to intestinal barrier disruption and the development of alcoholic steatohepatitis. However, long-term administration of Elafibranor significantly attenuated hepatic damage and intestinal barrier disruption, while restoring PPARα and PPARδ levels. This restoration was associated with improvements in autophagy dysfunction, apoptosis, inflammation, and lipid homeostasis.
These results suggest that Elafibranor regulates immune function, hepatic lipid metabolism, anti-inflammatory and antioxidant pathways, and autophagy and apoptosis mechanisms to mitigate ALD. Despite these promising findings, research on Elafibranor's efficacy in ALD is still limited, indicating a need for further studies to address existing gaps in the field.
Elafibranor in MAFLD: Recent research has led to the reclassification of non-alcoholic fatty liver disease to MAFLD, and non-alcoholic steatohepatitis is now termed MASH to better align with the current understanding of these conditions[4,20]. In severe cases, MAFLD can progress to liver fibrosis, cirrhosis, and even liver cancer, characterized by excessive fat accumulation in the liver, impaired liver function, and metabolic abnormalities[7,21]. Tølbøl et al[22] investigated the effects of Elafibranor in a choline-deficient L-amino acid-defined diet-induced MASH rat model. They found that Elafibranor intervention increased the expression of peroxisomal enzymes (ACOX1 and EHHADH) and significantly reduced the steatohepatitis score. While Elafibranor did not alleviate liver fibrosis histopathologically, it did decrease the expression of hydroxyproline and the fibrotrophic-related gene Col1a1.
In their study on late-stage MAFLD fibrosis in a mouse model, Perakakis et al[23] found that Elafibranor improved body weight, insulin sensitivity, and glucose homeostasis. It reduced levels of TG, diacylglycerol, and monoacylglycerol, promoted FA β-oxidation, and increased the phosphatidylcholine/phosphatidylethanolamine ratio, thereby enhancing lipid metabolism. Furthermore, Elafibranor stimulated methionine and glutathione metabolism, decreased linoleic acid ester-related metabolites (such as hydroxy-eicosatetraenoic acid and dihydroxy-eicosatetraenoic acid), increased eicosapentaenoic acid levels, and reduced arachidonic acid metabolites (including prostaglandin 2α and 6-keto-prostaglandin 1α). These effects contributed to the regulation of oxidative stress and inflammation.
Hakeem et al's study on Elafibranor's effects on MASH and colitis found that it inhibits the breakdown of the intestinal barrier and prevents macrophages from polarizing to the M1 type[24]. By disrupting the expression of intestinal compact junction proteins, Elafibranor reduces interferon-γ and inducible nitric oxide synthase production by M1 macrophages, which exacerbates inflammation. Additionally, Elafibranor enhances IL10/STAT3 signaling to promote M2-type macrophage polarization, aiding in anti-inflammatory responses and barrier repair. It also prevents TLR4/NF-κB activation in the liver, mitigating further liver damage following intestinal barrier collapse.
In their study on MASH models, Boeckmans et al[25] found that Elafibranor improves autophagy dysfunction and endoplasmic reticulum stress, alleviating MASH characteristics in vitro. Elafibranor also enhances lipid metabolism by downregulating liver X receptors and genes involved in very long-chain FA and fat synthesis, promoting FA β-oxidation. Moreover, Elafibranor prevents immune cell aggregation in vivo by upregulating inflammatory chemokines mediated by NF-κB, including CCL2, CCL7, CCL8, CXCL5, CXCL8, IL-1a, and IL-11.
In addition, Zhang et al[26] demonstrated that Elafibranor reduces steatosis, inflammation, and fibrosis in the liver of MASH mice. They proposed a regulatory mechanism where PPARδ activation decreases the E3 ubiquitin ligase ankyrin repeat and suppressor of cytokine signaling box-containing 2 protein (ASB2), leading to increased expression of S100 calcium-binding protein A4 (S100A4), which may promote fibrosis through epithelial-mesenchymal transition.
Collectively, these findings suggest that Elafibranor may ameliorate MAFLD through multiple mechanisms, including its anti-inflammatory effects, modulation of pro-fibrotic gene expression, enhancement of lipid and glucose metabolism, reduction of oxidative stress, regulation of immune responses, and correction of autophagy dysfunction.
Elafibranor in CLD: PBC is a chronic liver disease that, if untreated, can progress to cirrhosis, liver fibrosis, and cholestasis[27]. Elafibranor has demonstrated anti-cholestatic and anti-inflammatory properties in phase II trials involving PBC patients[28]. Significant reductions in alkaline phosphatase (ALP) levels, markers of PBC, and secondary inflammation indicators (IgM, γ-glutamyl transferase, 5'-nucleotidase, and high-sensitivity C-reactive protein) were observed. Importantly, Elafibranor did not worsen the pruritus commonly associated with PBC and was generally well tolerated. Recent phase III clinical trials further confirmed that Elafibranor rapidly and sustainably reduces ALP levels and improves dyslipidemia, including triglycerides and very low-density lipoprotein cholesterol[10].
Indeed, patients on Elafibranor therapy experienced a reduction in moderate-to-severe itching symptoms compared to those receiving other PBC therapies. This highlights Elafibranor's significant role in addressing PBC through its anti-inflammatory, anti-cholestatic, and lipid-metabolizing properties.
Future outlook
PPARα is predominantly expressed in the human liver, while PPARδ is found throughout all human tissues[29]. These receptors play crucial roles in metabolic processes such as inflammation, glucose balance, and lipid metabolism. Research indicates that Elafibranor can enhance high-density lipoprotein (HDL) cholesterol, reduce lipids and triglycerides, and activate PPARα, thereby promoting β-oxidative metabolism of FAs. Elafibranor also exhibits anti-inflammatory effects by reducing inflammation induced by lipopolysaccharides and cytokines[30]. Additionally, Elafibranor improves blood lipid profiles, increases HDL cholesterol levels, enhances insulin sensitivity, stimulates FA metabolism, and regulates hepatic and peripheral tissue metabolism through activation of PPARδ[8]. Importantly, Elafibranor does not induce the adverse effects associated with PPARγ receptor activation nor does it directly activate PPARγ receptors[31]. However, variations exist in the effects of PPARα and PPARδ activation across different tissues. Some studies suggest that PPARα activity impacts gut-related functions[32], while others indicate that PPARδ activation may influence liver-related functions[26], possibly due to variations in disease models used. Further research is necessary to fully elucidate these underlying mechanisms.
The gut-liver axis is vital for maintaining intestinal barrier integrity, liver function, and systemic inflammation[33]. Restoring this axis to its normal state is essential for improving intestinal and liver diseases. Normal function of the gut-liver axis depends on the integrity of the intestinal barrier, liver function, and the balance of intestinal flora. Disruption of any of these factors due to liver diseases can impair the normal function of the gut-liver axis[34]. Various liver diseases, including hepatic encephalopathy and chronic liver diseases, can arise from disruptions to the intestinal barrier[35,36]. The integrity of the intestinal barrier is heavily influenced by the gut microbiota. Disturbances in the structure and metabolism of intestinal flora can lead to degradation of the intestinal barrier and provoke an abnormal immune response[37]. With the rapid advancement of microbial 16S rRNA sequencing[38], exploring Elafibranor in the context of intestinal flora and intestinal homeostasis may shed light on its potential in managing liver diseases. Preliminary studies suggest that Elafibranor might positively impact liver diseases by modulating gut-related processes. Future research could further elucidate Elafibranor’s protective mechanisms in the gut, potentially revealing new therapeutic avenues for managing ALD, MAFLD, and CLD.
Elafibranor's potential for treating ALD, MAFLD, and CLD arises from its multi-target mechanism of action, which addresses various pathways involved in liver pathology. Its therapeutic efficacy may be further enhanced when used in combination with other therapeutic agents. Roth et al[39] found that combining Elafibranor with obeticholic acid in a mouse model of MASH improved therapeutic outcomes, suggesting that their complementary molecular mechanisms could synergistically target MASH. Similarly, Perakakis et al[23] highlighted the distinct but complementary anti-inflammatory and anti-fibrotic mechanisms of Elafibranor and liraglutide in MASH. Tølbøl et al[40] further explored the therapeutic effects of Elafibranor, obeticholic acid, and liraglutide in diet-induced obese mouse models of MASH, noting the unique anti-MASH properties of each. In the context of PBC, Lin et al[41] conducted a network meta-analysis which showed that PPAR agonists, including Elafibranor, improved biochemical outcomes such as ALP levels, especially when combined with ursodeoxycholic acid (UDCA). This suggests a potential benefit of combining Elafibranor with UDCA. Future research is necessary to fully assess the safety and efficacy of combining Elafibranor with other medications for liver diseases, as current studies mainly focus on treatment effectiveness.
