Regression of hepatic fibrosis after pharmacological therapy for nonalcoholic steatohepatitis

Abstract

The global incidence of nonalcoholic fatty liver disease (NAFLD) is escalating considerably. NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis, which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix, leading to fibrosis. Hepatocyte ballooning is a key catalyst for fibrosis progression, potentially advancing to cirrhosis and its decompensated state. Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD; therefore, those with substantial fibrosis require timely intervention. Although liver biopsy is the most reliable method for fibrosis detection, it is associated with certain risks and limitations, particularly in routine screening. Consequently, various noninvasive diagnostic techniques have been introduced. This review examines the increasing prevalence of NAFLD, evaluates the noninvasive diagnostic techniques for fibrosis, and assesses their efficacy in staging the disease. In addition, it critically appraises current and emerging antifibrotic therapies, focusing on their mechanisms, efficacy, and potential in reversing fibrosis. This review underscores the urgent need for effective therapeutic strategies, given the dire consequences of advanced fibrosis.

Key Words: Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Myofibroblasts; Fibrosis; Antifibrotic pharmacotherapy; Nonalcoholic fatty liver disease treatment strategies; Emerging treatments for nonalcoholic steatohepatitis

Core Tip: Non-alcoholic fatty liver disease (NAFLD) global incidence is escalating significantly. NAFLD covers a range of liver conditions, from simple steatosis to the more severe form known as non-alcoholic steatohepatitis, which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix, leading to fibrosis. Hepatocyte ballooning is a key catalyst for fibrosis progression.

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) is marked by the buildup of fat in liver cells, unrelated to alcohol consumption or medications that induce lipid build-up in hepatocytes. The diagnosis is confirmed when fat droplets are present in more than 5% of liver cells, or the liver's total fat content surpasses 5% of its total weight[1]. The worldwide prevalence of NAFLD is currently approximated at about 32.4%, increasing significantly from 25.5% before 2005 to 37.8% post-2016[2]. Currently, it is the most widespread chronic liver disease, affecting about 25% of the population[3]. The increasing occurrence mirrors the global increase in overweight and obesity cases, attributed to higher caloric intake than expenditure, leading to elevated body mass index (BMI)[4]. Consequently, NAFLD is quickly becoming the leading reason for cirrhosis, liver failure, and liver cancer, and is expected to be the foremost cause for liver transplants in the foreseeable future[5].

The spectrum of NAFLD encompasses isolated fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), which includes steatosis along with chronic inflammation and cellular damage. Histologically, NASH is marked by lobular inflammation and the swelling of liver cells, known as hepatocyte ballooning. This ballooning of hepatocytes is a critical factor in the progression of fibrosis, which can lead to cirrhosis and more severe liver disease. Notably, hepatocellular carcinoma (HCC) can arise even in non-cirrhotic stages of NAFLD[6]. Approximately 20% of NAFLD patients are likely to develop NASH within three to seven years[7], and between 9 and 25% of NASH patients may progress to cirrhosis over a span of 10 to 20 years[8].

Patients with NASH at stage ≥ F2 are prime candidates for pharmacological intervention and show the most potential benefit from antifibrotic treatments (Table 1). Conversely, stage F1 fibrosis often regresses with lifestyle modifications and management of associated metabolic conditions[9]. Accurate diagnosis of the fibrosis stage, ideally through non-invasive techniques, is crucial. Furthermore, the primary goal in clinical trials for antifibrotic drugs should be the regression of advanced fibrosis[10]. Thus, this review will concentrate on the methods for staging liver fibrosis and the efficacy of antifibrotic medications in reducing advanced fibrosis.

Table 1 Pharmacological agents for non-alcoholic steatohepatitis.

Drug	Mechanism of action	Side effects	Stage of clinical trials
Vitamin E	Antioxidant, reduces oxidative stress, modulates NF-kB pathway	Nausea, diarrhea, increased bleeding risk, prostate cancer concerns	Approved for use in NAFLD/NASH, widely recommended
GLP-1 RAs (e.g., Semaglutide, Liraglutide)	Increases insulin secretion, suppresses glucagon, reduces steatosis and inflammation	Nausea, diarrhea, risk of pancreatitis	Phase II and III trials ongoing
Pioglitazone	Activates PPAR-γ, improves insulin sensitivity, reduces liver fat	Weight gain, fluid retention, bone loss, risk of heart failure	Phase II and III trials completed
Obeticholic Acid	FXR agonist, reduces hepatic inflammation and fibrosis, promotes bile secretion	Pruritus, dyslipidemia (increased LDL, decreased HDL), fatigue	Phase III trials (REGENERATE study)
Lanifibranor	Pan-PPAR agonist, modulates lipid metabolism, reduces inflammation	Fatigue, nausea, diarrhea	Phase III trials ongoing
Saroglitazar	Dual PPAR-α/γ agonist, reduces liver fat, improves insulin resistance	Gastrointestinal symptoms, rash	Phase II trials ongoing
Cenicriviroc	CCR2/CCR5 antagonist, reduces liver inflammation and fibrosis	Fatigue, diarrhea, headaches	Phase III trials (AURORA study)
Selonsertib	ASK1 inhibitor, reduces fibrosis and inflammation	Nausea, diarrhea, fatigue	Failed in Phase III trials

NAFLD: Nonalcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; GLP-1 RAs: Glucagon-like peptide-1 receptor agonists; PPAR: Peroxisome proliferator-activated receptor; FXR: Farnesoid X receptor; LDL: Low-density lipoprotein; HDL: High-density lipoprotein.

DIAGNOSING LIVER FIBROSIS

The degree of fibrosis is the primary predictor for the progression of liver conditions and mortality and further acts as a crucial marker for the emergence of additional health issues, such as heart diseases and type 2 diabetes (T2DM), which emphasizes the need for the accurate diagnosis of this condition[11].

Liver biopsy

Although regarded as the definitive method for diagnosing the stage of fibrosis and for histologically evaluating NAFLD[1], liver biopsy is not appropriate for widespread screening[12]. Its primary use is to differentiate between NASH and NAFL and is currently the main standard for its diagnosis[13,14]. However, liver biopsy is associated with several complications, including pain in up to 84% of patients and serious complications in 0.3%-0.57% of cases. Mortality is rare but can occur in about 0.01% of cases[14]. Although various histological scoring systems are available to categorize liver biopsy samples[15], tissue samples obtained are of limited size and are subject to a high degree of sampling variability. Consequently, studies have documented discrepancies of one fibrosis stage out of five possible stages in 40% of patients with NASH when comparing adjacent large biopsies or samples from different liver lobes[16,17] (Table 2).

Table 2 Diagnostic techniques for liver fibrosis in nonalcoholic fatty liver disease/non-alcoholic steatohepatitis.

Diagnostic technique	Method	Advantages	Limitations
Liver biopsy	Invasive procedure, histological assessment	Gold standard, provides detailed fibrosis staging	Invasive, sampling variability, associated risks
Vibration-controlled transient elastography	Ultrasound-based, measures liver stiffness	Non-invasive, widely used	Less accurate in obese patients, influenced by inflammation
MRE	MRI-based imaging, measures tissue stiffness	More accurate than Fibroscan for fibrosis and steatosis	High cost, limited availability
APRI	Blood-based, calculates fibrosis risk	Non-invasive, low cost	Lower sensitivity in early fibrosis
ELF test	Blood-based, measures biomarkers of fibrosis	High sensitivity and specificity for advanced fibrosis	Costly, limited access in some regions

APRI: Aminotransferase-to-platelet ratio index; MRE: Magnetic resonance enterography; ELF: Enhanced liver fibrosis; MRI: Magnetic resonance imaging.

Liver stiffness measurement

Vibration-controlled transient elastography: This method involves measuring the stiffness of the liver, a physical property affected by the fibrosis stage[18]. A meta-analysis by Hsu et al[19] using stiffness thresholds of 6.2, 7.6, 8.8, and 11.8 kPa yielded area under the receiver operating characteristic (AUROC) curve values of 0.82, 0.87, 0.84, and 0.83 (with 95%CI), respectively, for identifying fibrosis stages ≥ F1–F4.

Other noninvasive ultrasound-based elastography methods: Various ultrasound-based techniques are available to measure liver elasticity[20], which employ either shear wave or strain imaging. Strain imaging encompasses techniques such as acoustic radiation force impulse imaging and strain elastography[21]. Shear-wave imaging, used in devices such as fibroscan R, is another technique[22]. Although these methods need further research, especially regarding their application in NAFLD, their accuracy is being documented more often and they are gaining attention in clinical settings[23].

Magnetic resonance elastography: Magnetic resonance elastography (MRE) is a technique based on magnetic resonance imaging that quantifies the stiffness of tissues. For diagnosing liver fibrosis and steatosis, MRE is more accurate than controlled attenuation parameter and vibration-controlled transient elastography methods. Nonetheless, owing to the substantial expense associated with it, MRE is not commonly employed for regular screening in patients with NAFLD[24].

Noninvasive scores for liver fibrosis detection: Several noninvasive scoring systems based on standard laboratory and clinical data have been developed to assess fibrosis risk. The aspartate aminotransferase to platelet ratio index, originally designed for hepatitis C, is now also utilized to predict significant fibrosis in NASH[25]. A study by Xiao et al[26] reported that the AUROC of NAFLD fibrosis score for excluding advanced fibrosis was 0.78[26]. The fibrosis-4 score demonstrated an AUROC of 0.80 for advanced fibrosis, with a specificity of 79%, sensitivity of 77%, negative predictive value of 84%, and positive predictive value of 66%.

The enhanced liver fibrosis (ELF) test, which incorporates markers such as HA, PIIINP, and TIMP1, has been shown to be effective for the noninvasive diagnosis of advanced fibrosis in NAFLD[27-29]. Vali et al[27]’s meta-analysis verified the effectiveness of the ELF test in detecting substantial fibrosis, with a sensitivity of 93% at a cutoff of 7.7, although a higher specificity was achieved at a cutoff of 9.8. The FibroMeters series, developed by Echosens for various chronic liver diseases[30], encompasses the FibroMeter NAFLD and the FibroMeter V2G. The latter, initially created for hepatitis C, has shown enhanced accuracy in NAFLD, with AUROCs of 0.76 and 0.80 for detecting F ≥ 3 fibrosis. Moreover, the MRI-based MAST score outperformed earlier models in noninvasively detecting patients at an increased risk of fibro-NASH[31].

MANAGEMENT OF NAFLD AND NASH

Reversing advanced fibrosis and preventing its progression to cirrhosis in patients identified to be rapid progressors are critical in reducing liver-related mortality. However, managing NASH in patients with stage 1 fibrosis with antifibrotic treatments may have limited value as mild fibrosis can either remain stable or potentially regress when minor lifestyle modifications are made or when the metabolic syndrome is effectively managed[32].

The cornerstone of NAFLD management involves lifestyle interventions, such as weight loss and increased physical activity. Reducing body weight by 3%–5% can improve steatosis. More significant weight loss achieved via lifestyle modifications can lead to improvements in the histological features of NASH too. Patients who achieve a weight loss of ≥ 10% of their body weight experience the most significant improvements in alleviating NAFLD activity score (NAS), resolving NASH, and regressing fibrosis[33]. Nonetheless, maintaining these changes can be challenging. Bariatric surgery is a viable alternative, especially in improving insulin resistance and hyperinsulinemia as these contribute to fibrosis in NAFLD[34]. Lassailly et al[35] observed that bariatric surgery resulted in NASH resolution in approximately 85% of the patients, with a reduction in disease pathology after 1 year of follow-up. This finding suggests its potential value in patients with morbid obesity who are unresponsive to lifestyle adjustments. The long-term effects of bariatric surgery in this group of patients require additional research.

Despite advancements in understanding the cellular and molecular basis of liver fibrosis in the recent years, no medications have specifically been authorized for fibrosis treatment by the European Medicines Agency (EMA) or the Food and Drug Administration (s)[36]. International guidelines recommend that drug therapy for NAFLD/NASH be limited to patients with active disease and liver fibrosis at stage ≥ 2[37,38]. Moreover, the FDA and EMA have established two goals for approving drugs in patients with noncirrhotic ≥ H: Resolution of NASH without advancing fibrosis and a minimum of a single-stage reduction in liver fibrosis without exacerbation of NASH[38].

CURRENT OPTIONS FOR NAFLD TREATMENT

In addition to vitamin E, medications primarily used for T2DM and obesity management are also recommended for NAFLD treatment. These drugs directly influence NASH, which in turn could indirectly lead to the regression of fibrosis. However, direct antifibrotic effects are also possible owing to the close association between NASH and fibrosis[39]. Vitamin E, particularly the alpha-tocopherol form, acts as an antioxidant by reducing oxidative stress in the liver, scavenging free radicals, and modulating the NF-kB pathway, crucial for regulating inflammation and apoptosis in hepatic cells. However, high-dose supplementation can lead to side effects such as nausea, diarrhea, and increased bleeding risks. Prolonged use may also raise concerns regarding increased mortality and prostate cancer risks, necessitating careful therapeutic consideration[40].

In the treatment of T2DM, medications that have demonstrated positive impacts on the histological features of NAFLD include sodium–glucose cotransporter-2 inhibitors, thiazolidinediones (TZDs), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs).

GLP-1 RAs, such as semaglutide and liraglutide, enhance glycemic control via mechanisms such as insulin secretion, glucagon suppression, satiety enhancement, and delayed gastric emptying. These actions occur through the activation of GLP-1 receptors on pancreatic beta cells, which stimulate cyclic AMP production and promote insulin secretion through pathways involving protein kinase A and Epac2[41]. Additionally, GLP-1 RAs improve hepatic markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase[39]. Wilding et al[42] observed that a regimen of 2.4 mg semaglutide weekly combined with lifestyle interventions led to significant weight reduction in overweight and obese participants. Despite these benefits, common side effects of GLP-1 RAs include gastrointestinal issues like nausea, diarrhea, and a rare risk of pancreatitis[41]. The LEAN trial was focused on assessing the effectiveness of liraglutide, a type of GLP-1 RA, specifically in terms of NASH regression without exacerbating fibrosis. Although notable improvements were seen in NASH resolution, no significant changes were observed in fibrosis scores[43]. In a separate study involving semaglutide, another GLP-1 RA, patients at risk for NAFLD were treated for 104 weeks with doses of 0.5 mg or 1.0 mg weekly. Remarkably, semaglutide lowered ALT levels from the 28^th to the 20^th week of treatment[44]. Nevertheless, despite its substantial impact on resolving NASH, semaglutide, like liraglutide, did not achieve the targeted improvement in fibrosis after 72 weeks of therapy[45].

TZDs such as pioglitazone primarily target peroxisome proliferator-activated receptors (PPARs), particularly the PPAR-γ isoform. This receptor, when linked with the retinoid X receptor, exerts potent insulin-sensitizing effects in fat tissues and further decreases steatosis[46]. Pioglitazone works by activating PPAR-γ, a nuclear receptor involved in fat cell differentiation and lipid metabolism. This activation enhances peripheral glucose uptake, reduces insulin resistance, and increases the transcription of genes involved in lipid storage and metabolism. Additionally, PPAR-γ modulates inflammatory pathways by reducing the expression of pro-inflammatory genes, which contributes to its antifibrotic effects. The signaling cascade involves translocation of PPAR-γ to the nucleus, binding to DNA response elements, and altering gene transcription, leading to improved metabolic function and potentially reduced liver fibrosis[47]. TZDs are known to reduce liver fat content, although they might contribute to a slight overall increase in body weight. This reduction in liver fat is indicative of improved adipose tissue functioning, which corresponds to the shift of fat from visceral to subcutaneous storage[48]. In addition, PPAR-γ modulates the activation of hepatic stellate cells, which signifies that TZDs could directly influence fibrogenesis. Owing to the histological enhancements observed with pioglitazone, various guidelines support its use in treating patients with NASH confirmed via liver biopsy who also have T2DM[49]. However, the PIVENS trial, which evaluated 30 mg/day pioglitazone over 96 weeks, did not observe any significant improvement in fibrosis stages compared with a placebo[50]. The primary adverse effects of pioglitazone include weight gain, fluid retention, pedal edema, and the risk of bone loss, with the potential to exacerbate congestive heart failure in susceptible individuals. Importantly, there has been no associated increase in cardiovascular disease or all-cause mortality[51]. Although pioglitazone (a TZD) and semaglutide (a GLP-1 RA) were effective in resolving NASH, neither significantly reduced fibrosis by at least one stage. However, a decline in average fibrosis scores was noted[52,53]. In patients with T2DM treated with dapagliflozin or empagliflozin, a decrease in liver fat was observed, but these treatments did not affect liver fibrosis[54,55]. Mantovani et al[56]’s meta-analysis confirmed the effect of these drugs on steatosis, but histological response data from randomized placebo-controlled trials are still awaited[57].

Several pharmaceutical agents, such as lanifibranor, pirfenidone (PFD), cenicriviroc (CVC), and saroglitazar, are undergoing trials for their potential to treat liver fibrosis. Lanifibranor, also known as IVA337, is a pan-PPAR agonist that activates all three PPAR isoforms (α, γ, δ). This activation promotes insulin sensitivity, decreases inflammation, and modulates lipid metabolism in the liver, which are crucial for improving liver health in conditions like NASH. By enhancing the transcription of genes involved in fatty acid oxidation and glucose homeostasis, lanifibranor helps reduce liver fibrosis and inflammation. In clinical studies, patients treated with a 1200 mg dosage exhibited a substantial decline in the SAF-A score, a composite measure of steatosis, activity, and fibrosis severity, indicating fibrosis reduction compared with those who received a placebo[58,59]. Currently advancing to phase III trials, lanifibranor has shown promising results in the resolution of NASH as well as the amelioration of fibrosis[60,61].

In a controlled trial involving 106 individuals diagnosed with NAFLD/NASH, the administration of 4 mg once daily Saroglitazar, a dual PPAR agonist targeting both PPAR-α and PPAR-γ, led to notable improvements in ALT levels, liver fat content, insulin resistance, and atherogenic dyslipidemia after 16 weeks of therapy. Saroglitazar also deactivates the hepatic LPS/TLR4 signaling pathway, significant for controlling inflammatory responses in the liver. Furthermore, the study revealed a significant reduction in liver fibrosis, as evidenced by fibroscan measurements, which highlights the efficacy of saroglitazar in mitigating liver fibrosis in patients with NAFLD and diabetic dyslipidemia[62-65].

PFD operates primarily by suppressing the production of pro-fibrotic growth factors like transforming growth factor-beta (TGF-β), which plays a central role in fibrosis development. Additionally, it inhibits pro-inflammatory pathways involving cytokines such as tumour necrosis factor alpha and interleukin-1β. Pirfenidone’s action helps reduce fibrosis and inflammation not only in the lungs but potentially in other organs like the liver. It also modulates pathways such as Wnt/GSK-3β/β-catenin, which are critical for cell growth and fibrosis. In the PROMETEO study, an extended-release formulation (600 mg twice daily) combined with standard care was evaluated in patients with advanced liver fibrosis, showing a significant reduction in fibrosis in 35% of participants. While generally well tolerated, common side effects include gastrointestinal symptoms like nausea and rash, as well as photosensitivity and liver enzyme alterations[66,67].

CVC acts as a dual antagonist for the C-C chemokine receptors CCR2 and CCR5, which are involved in immune cell recruitment to liver inflammation sites. By blocking these receptors, CVC reduces the migration of pro-inflammatory cells to the liver, potentially decreasing liver inflammation and subsequent fibrosis. This is achieved by inhibiting chemokine pathways involving MCP-1 (for CCR2) and RANTES (for CCR5). Although a phase II trial showed a 9.6% reduction in fibrosis after one year, this significance was not maintained over two years. The phase III AURORA trial is currently underway to further assess the efficacy of 150 mg CVC in treating patients with NASH and stage F2 or F3 fibrosis. Side effects commonly associated with CVC include fatigue, diarrhea, and headaches[68-72].

To date, obeticholic acid (OCA) is the only medication that has shown efficacy in a phase III trial for this specific endpoint. OCA is a potent and selective agonist of the farnesoid X receptor (FXR), a nuclear receptor regulating bile acid, glucose, and lipid metabolism. By activating FXR, OCA reduces bile acid synthesis, promotes bile secretion, and decreases hepatic inflammation and fibrosis. FXR activation downregulates bile acid synthesis by suppressing the CYP7A1 enzyme, crucial for bile acid production, and induces the production of fibroblast growth factor 19, which helps regulate glucose homeostasis and lipid metabolism. This mechanism is vital for liver regeneration and reducing hepatic inflammation. The FDA approved OCA in 2016 for treating primary biliary cholangitis, and it is now undergoing a phase III trial (REGENERATE study) to assess its effectiveness and safety for NAFLD. An initial analysis from the REGENERATE study indicated that OCA led to a significant regression in fibrosis by at least one stage, showing an 11% effect size after 72 weeks at a 25 mg dose. However, it did not attain the predefined endpoint for resolving NASH. Common side effects include pruritus, fatigue, headache, and dyslipidemia [increased low-density lipoprotein (LDL) cholesterol, decreased high-density lipoprotein cholesterol]. Pruritus is dose-dependent and more frequent at higher doses. OCA has been associated with increased serum cholesterol levels, particularly LDL, which may require the use of statins for lipid management[73,74].

Several compounds, despite positive preclinical outcomes, have not been successful in clinical trials. For example, Selonsertib, which inhibits apoptosis signal-regulating kinase 1, initially demonstrated potential in alleviating fibrosis, steatosis, and the progression to cirrhosis in patients with moderate-to-severe NASH[75]. Yet, in multiple phase III clinical trials, it failed to meet the specified endpoints for fibrosis reduction[76]. A similar scenario occurred with simtuzumab, a monoclonal antibody targeting lysyl oxidase-like 2, which is involved in fibrogenesis. The drug did not show efficacy in reducing fibrosis during phase IIb trials[77]. Moreover, the galactin-3 inhibitor GR-MD-02 was not effective in NASH and liver fibrosis reduction in phase II trials[78,79]. Elafibranor, a dual PPAR agonist, initially showed potential in alleviating NASH and liver fibrosis in a phase II trial. A phase III trial (RESOLVE-IT), which included 2000 patients with F2–F3 NASH was conducted based on the results of phase II. However, in an interim analysis at 72 weeks, NASH improvement without fibrosis worsening as the primary endpoint was not attained in this study[80].

Resmetirom, an oral thyroid hormone receptor beta-selective agonist that targets the liver, has shown promising results in a recent phase III trial for treating NASH. In this study, participants with biopsy-confirmed NASH and liver fibrosis stages F1B–F3 received resmetirom at either 80 mg or 100 mg daily or a placebo. After 52 weeks, significant improvements were observed in the resmetirom groups, with NASH resolution rates of 25.9% for the 80 mg dose and 29.9% for the 100 mg dose compared with 9.7% for the placebo. Furthermore, 24.2% of the patients in the 80 mg group and 25.9% in the 100 mg group reached at least a one-stage reduction in fibrosis, which was significantly higher than the 14.2% noted in the placebo group. Side effects, including diarrhea and nausea, were more common in the resmetirom groups, while serious adverse events occurred at similar rates across all groups. Resmetirom also showed beneficial effects on lipid metabolism, with significant reductions in LDL cholesterol. This finding confirms the potential efficacy of the drug in resolving NASH and reducing fibrosis in patients with advanced stages of liver disease[81].

Future therapeutic targets

Emerging therapeutic opportunities may reside within the gut microbiome, a key player in the process of fibrogenesis. Targeting the gut–liver axis (GLA) via modifications of the gut microbiome is becoming a preferred strategy for treating NAFLD[82]. Experimental studies in mice have demonstrated that the removal of the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) worsens liver steatosis and fibrosis. This finding implies that NOD2 interacts with GLA to mitigate steatosis, fibrosis, and imbalances in the gut microbiota[83].

Moreover, targeting the platelet-derived growth factor (PDGF) signaling pathway, which is vital in liver fibrogenesis, is another promising therapeutic approach. The PDGF signaling can be disrupted in several ways, such as modulating its isoforms, altering receptor binding, and directly inhibiting the pathways. Blocking the activity of PDGF receptor kinases is one of the most effective strategies. However, kinase inhibitors developed to date often lack specificity[84].

CONCLUSION

The ongoing challenge of liver fibrosis in NAFLD highlights the need for therapies that can reverse or halt the progression of fibrosis to prevent serious liver complications, such as cirrhosis and HCC. Although liver biopsy is the gold standard for evaluating fibrosis stages, emerging noninvasive diagnostic methods offer a viable alternative to monitor disease progression and determine therapeutic effectiveness. Current investigations on antifibrotic drugs have shown potential not only for delaying the progression of cirrhosis but also for improving overall liver health. Comprehending the mechanisms that underlie NAFLD-related fibrosis is vital for developing targeted therapies that can significantly alleviate liver damage and improve patient outcomes.