The Role of FGF1 in Chronic Liver Diseases

1. Introduction

Chronic liver disease (CLD) represents a major global public health challenge, imposing an enormous social and economic burden with high morbidity and mortality worldwide. Approximately 2 million people die from liver diseases each year [1], and the quality of life of affected patients is severely impaired, accompanied by increased risks of various complications, heavy medical expenses, and significant loss of disability-adjusted life years [2]. Among those aged 25 to 49, liver diseases are the 12th leading cause of disability-adjusted life years, and this potential loss of life is even higher in developed regions like Europe [3,4]. Historically, hepatitis virus infection has been the primary cause of CLD, but with the popularization of vaccination and the application of targeted therapeutic drugs, its proportion is gradually declining. Instead, drug-induced liver injury (DILI), alcohol-related liver disease (ALD), metabolic-associated fatty liver disease (MAFLD), and primary sclerosing cholangitis (PSC) have emerged as the predominant etiologies of CLD in many developed areas, and some of these diseases still lack specific and effective targeted therapeutic drugs [1,5,6,7]. The complex pathogenesis of CLD involves multiple pathways including oxidative stress, lipid metabolism disorder, mitochondrial dysfunction, immune response abnormality, and bile acid homeostasis imbalance, highlighting the urgent need to explore novel regulatory molecules and therapeutic targets for the development of effective intervention strategies.

Fibroblast Growth Factor 1 (FGF1), also known as acidic FGF (aFGF), is a small polypeptide with a molecular weight of approximately 17-18 kDa. Distinguished from classic secretory proteins, FGF1 lacks a typical secretory signal peptide and is secreted by cells into the extracellular space via a paracrine pathway, exerting biological functions by binding to fibroblast growth factor receptors (FGFR) and heparan sulfate proteoglycan as an auxiliary factor [8,9]. Uniquely, FGF1 is the only protein in the FGF family that can bind to all four FGFR subtypes (FGFR1 to FGFR4), enabling it to activate multiple downstream signaling pathways and regulate diverse physiological and pathological processes [10,11]. Through activating the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, FGF1 modulates metabolic regulation, glucose uptake, and cell survival [12]. By activating the Ras/mitogen-activated protein kinase (MAPK) pathway, FGF1 promotes cell proliferation and differentiation, and supports tissue repair and metabolic regulation [13,14]. Via the phospholipase C γ (PLCγ) pathway, FGF1 promotes intracellular calcium signal transduction and activation of protein kinase C (PKC), thereby regulating gene expression and cellular metabolism [15]. Additionally, FGF1 regulates cell migration, differentiation, proliferation, apoptosis and wound healing by increasing the phosphorylation level of STAT3 [16]. As a crucial metabolic regulatory molecule, FGF1 is widely expressed in various tissues of the body, and accumulating studies have demonstrated its important regulatory roles in the occurrence and development of multiple CLDs, either exerting protective effects by alleviating liver injury or participating in disease progression by regulating biliary response and fibrosis, making it a potential therapeutic target for CLD.

2. The Role of FGF1 in Drug-Induced Liver Injury

Drug-induced liver injury (DILI) refers to liver damage caused by drug exposure. Its clinical manifestations and pathological mechanisms vary with drug characteristics, dosage, exposure duration, and host-specific factors [17]. The identified mechanisms include mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, hepatocyte apoptosis /necrosis, and immune-mediated bile duct damage [18]. The etiologies of DILI exhibit regional differences: antiretroviral drugs, anti-tuberculosis drugs and herbal medicines are the main causes of DILI in Asia and Africa, while antibiotics, non-steroidal anti-inflammatory drugs and psychotropic drugs predominate in Europe and the United States [19].

The long course of tuberculosis and the hepatotoxicity of anti-tuberculosis drugs have made anti-tuberculosis DILI one of the most common types of DILI [20]. The risk of liver toxicity for first-line anti-tuberculosis drugs, such as isoniazid and rifampicin, ranges from 2% to 28% [21], which may lead to adjustments or interruptions in the anti-tuberculosis treatment and can even cause acute liver failure and even death in severe cases [22]. The mechanisms of hepatotoxicity associated with isoniazid and rifampicin include reduced bile acid transporters, leading to bile acid accumulation and disruption of the Bcl-2/Bax balance in hepatocytes, release of cytochrome c, and triggering of cell apoptosis [23]. Lin et al. found that serum total bile acid levels significantly increase and the liver FGF1 expression levels decrease in mice treated with isoniazid and rifampicin, and that exogenous FGF1 administration can restore the bile acid homeostasis and alleviate the liver damage [20]. Further research has revealed the FGF1 can act as a negative regulator of bile acid synthase, inhibiting its expression through the FGFR4-ERK1/2-HNF4 signaling pathway [20].

Acetaminophen, a widely used analgesic and antipyretic, can cause to severe liver damage or even death [24,25]. Excessive acetaminophen leads to the formation of excessive NAPQI in the liver, which depletes large amounts of glutathione and forms toxic protein adducts, further inducing mitochondrial dysfunction, oxidative stress, inflammation, and DNA damage [26,27,28,29]. Under conditions of acetaminophen overdose, mouse serum ALT and AST levels significantly increased, with severe inflammation, apoptosis, oxidative stress, and endoplasmic reticulum stress observed in hepatocytes, including elevated inflammatory factors IL-6 and TNF-α, upregulation of pro-apoptotic protein Bax, and downregulation of anti-apoptotic protein Bcl-2. Injection of FGF1 could reverse these pathological changes [30]. Currently, N-acetylcysteine is the only approved antidote for acetaminophen overdose, but its treatment window is relatively short, making FGF1 a promising alternative intervention strategy [31].

Doxorubicin (DOX), a broad-spectrum anti-tumor drug, directly damages the liver (the main organ involved in the metabolism and detoxification) through ROS-induced oxidative stress [32,33]. The use of DOX leads to decreased body weight and liver weight, increased ALT and AST in mice, which is more severe in FGF1 knockout mic [34]. FGF1 deficiency reduces Nrf2-mediated antioxidant gene expression, increases 3-nitroso modification of various proteins and liver malondialdehyde content, further exacerbating oxidative stress and liver damage [34]. Exogenous FGF1 administration can alleviate DOX-induced liver injury, inflammation, and hepatocyte apoptosis, and can synergize with resveratrol to enhance its protective effect against liver injury [35].

Given the limited clinical treatment options for DILI (mostly only drug withdrawal) [17], FGF1 is expected to become a precise intervention target for DILI therapeutic drug development.

3. The Role of FGF1 in Metabolic Liver Diseases

Metabolic associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has undergone a name change that highlights the bidirectional interaction between fatty liver and metabolic changes, and emphasizes that its onset excludes alcohol consumption and other independent liver disease factors [36]. MAFLD is the most prevalent metabolic CLD, affecting approximately 25% of the global population, with a projected increase to 33.5% of adults by 2030 [37,38,39]. It is characterized by hepatic steatosis accompanied by at least one cardiometabolic risk factor, such as obesity, type 2 diabetes, hypertension or dyslipidemia. Its core pathogenesis involves lipid metabolism disorder, mitochondrial dysfunction, oxidative stress, insulin resistance, and hyperinsulinemia [40]. FGF1 exerts a multifaceted protective effect on MAFLD through regulating these key pathological links.

Dysregulation of liver lipid metabolism can lead to hepatic steatosis resulting from disrupted balance between fatty acid uptake, fat synthesis, oxidation, and output which results from of hepatic steatosis. Fat synthesis is mainly regulated by the transcription factor SREBP1, which promotes lipid accumulation by regulating the expression of downstream fatty acid synthase (FAS), stearoyl CoA Desaturase-1 (SCD-1) and other fat synthesis related enzymes [41,42]. Fat oxidation is regulated by peroxisome proliferator activated receptor alpha (PPARα), which enhances fat oxidation by activating genes involved in mitochondrial, peroxisome, and endoplasmic reticulum lipid oxidation, and thereby avoiding excessive liver fat accumulation [43]. FGF1 treatment of MAFLD mice can effectively reduce hepatic steatosis, and serum AST and ALT levels by downregulating SREBP1 expression and upregulating PPARα expression, thereby weakening fat synthesis and enhancing fat oxidation [44,45].

Mitochondrial dysfunction plays an important role in MAFLD progression. Excessive lipid accumulation induces mitochondrial dysfunction, impairing energy production, reducing oxidative capacity, and increasing ROS generation [46]. These ROS can further damage mitochondrial β-oxidation function and consume mitochondrial antioxidants such as glutathione, thereby exacerbating mitochondrial damage and forming a vicious cycle [47,48]. In MAFLD mice, FGF1 treatment significantly promotes Nrf2 nuclear translocation, and increases the expression of downstream antioxidant enzymes such as NAD(P)H dehydrogenase, counteracting oxidative damage caused by lipid overload [45].

There is a bidirectional relationship between MAFLD and metabolic diseases: obesity and diabetes patients have a higher prevalence of MAFLD, and vice versa [49]. Improving metabolic diseases plays an important role in the treatment and prognosis of MAFLD [50]. FGF1 has been reported to improve lipid metabolism and maintain glucose homeostasis in diabetes and obesity in recent years [51,52]. FGF1 improves insulin resistance by increasing insulin receptor substrate 1 (IRS1) phosphorylation, phosphatidylinositol 3-kinase (PI3K) pathway, and promoting translocation of type 4 glucose transporter (GLUT4) to the cell membrane, thereby enhancing cellular glucose uptake, and maintaining glucose homeostasis [53,54]. Collectively, the multifaceted protective effect of FGF1 makes a potential target for MAFLD treatment.

4. The Role of FGF1 in Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a progressive chronic cholestatic CLD characterized by intrahepatic and/or extrahepatic bile duct injury, manifested as bile duct inflammation, fibrosis, and stenosis, which eventually progresses to liver cirrhosis and end-stage liver failure [55]. Its pathogenesis is not yet fully understood, and is believed to be driven by a combination of genetic susceptibility, environmental exposure, abnormal immune responses, bile acid homeostasis disturbance, and gut microbiota dysbiosis [56]. Unlike its protective role in MAFLD, FGF1 plays a promotive role in PSC progression by regulating biliary response and liver fibrosis. Research has found that in a PSC mouse model, FGFR1-4 are upregulated in bile duct cells, which exhibit immunoreactivity to FGF1. Exogenous FGF1 exacerbates ductal response, liver inflammation, and fibrosis, while inhibition of the FGF1/FGFR signaling axis (via FGFR inhibitors or FGF1 monoclonal antibodies) effectively alleviates these pathological changes [57]. The underlying mechanism is that FGF1 upregulates the expression of Senescence-Associated Secretory Phenotype (SASP) and TGF-β1, which induces biliary proliferation/ductal response and biliary aging, and subsequently activates hematopoietic liver cells and liver fibrosis through paracrine mechanisms. Targeting the FGF1/FGFR signaling axis can reduce biliary aging, SASP release, and ductal response, thus mitigating PSC-related liver injury and fibrosis [57,58,59], indicating that this axis is a novel potential therapeutic target for PSC intervention.

Currently, PSC still lacks effective treatment methods, and combination drug therapy targeting multiple pathogenic aspects, including the FGF1/FGFR signaling axis , may provide new opportunities [60].

5. FGF1 and Alcohol-Related Liver Disease

Alcohol-related liver disease (ALD) is a common CLD caused by long-term heavy alcohol consumption, which progresses from alcoholic fatty liver and mild ALD to alcoholic hepatitis, liver fibrosis, and cirrhosis [61,62]. In 2021, the global number of ALD patients reached approximately 3.02 million (a 38.68% increase compared to 2000), the number of alcohol-related primary liver cancer patients was about 132,000 (a 94.12% increase compared to 2000), and the numbers of deaths from ALD and from alcohol-related primary liver cancer were 354,250 and 92,230, respectively (a 32.6% and a 76.75% increase compared to 2000) [63]. The complex pathogenesis of ALD involves multiple interrelated pathways including oxidative stress, abnormal lipid metabolism, endoplasmic reticulum stress, autophagy, multiple cell death modes, gut microbiota dysbiosis, and abnormal liver immune response [64]. Although there are currently no direct experimental studies on the role of FGF1 in ALD, based on its well-documented biological functions in other CLDs, FGF1 is hypothesized to exert a protective role in ALD. FGF1’s ability to alleviate oxidative stress (via Nrf2 antioxidant pathway activation), regulate lipid metabolism (via SREBP1/PPARα modulation), and inhibit hepatocyte apoptosis and inflammation suggests that it may target multiple key pathological links of ALD to alleviate alcohol-induced liver injury and fibrosis. This hypothesis provides a critical research direction for subsequent studies on the regulatory role and mechanism of FGF1 in ALD, and confirmation of this hypothesis will provide a new potential therapeutic target for ALD, a disease that currently lacks approved specific drugs globally.

To provide a concise overview, the key mechanisms of FGF1 in different types of CLD are summarized in Table 1.

6. Discussion and Prospect

Some CLDs, such as ALD and anti-tuberculosis drug-induced liver damage, still lack FDA and EMA approved therapeutic drugs globally. The high prevalence of ALD and the clinical dilemma between liver injury treatment and anti-tuberculosis treatment make it crucial to search for new therapeutic targets and develop specific drugs. FGF1, as an important metabolic regulatory molecule, is expected to become a promising new target. Currently, FGF family members (FGF21, FGF19) have entered clinical trials, providing a valuable reference for the future development of FGF1-based CLD therapeutics.

However, the potential mitogenic activity of FGF1 may pose a risk of tumorigenesis, which is a key challenge for its clinical translation. Fortunately, the N-terminal deficient FGF1 analogue (FGF1Δ) retains metabolic regulatory functions (e.g., hypoglycemic effect) while exhibiting low mitogenic activity in vitro, providing a feasible strategy for the development of safer FGF1-based drugs [65]. Future research should focus on clarifying the tissue-specific and disease-specific regulatory mechanisms of FGF1 in CLDs, conducting in-depth safety evaluations and metabolic pathway studies, and developing FGF1 analogues or targeted modulators with strong CLD therapeutic effects and minimal side effects. In addition, further experimental verification of the protective effect and mechanism of FGF1 in ALD is urgently needed to provide a theoretical basis for its clinical application in ALD treatment. With the continuous deepening of research, FGF1 is expected to provide a new direction for the precise treatment of CLDs and bring new hope for patients with these currently difficult-to-treat liver diseases.