Silymarin: A Natural Compound for Obesity Management

Abstract

Silybum marianum (L.) Gaertn, commonly known as milk thistle, is an herbal medicine rich in silymarin, a bioflavonoid complex. Historically, silymarin was used for treating liver diseases, but recent studies highlight silymarin’s potential for obesity management. This narrative review aims to provide an in-depth examination of the existing knowledge of Silybum marianum (L.) and its secondary compounds concerning obesity and associated comorbidities, summarizing data from in vitro, preclinical, and clinical studies. Obesity is a significant public health issue, exacerbated during the COVID-19 pandemic, as a major risk factor for mortality. It contributes to metabolic dysfunction, including oxidative stress, metainflammation, cardiovascular diseases, and type 2 diabetes development. Silymarin has demonstrated benefits on insulin signaling and lipid metabolism, as well as antioxidant and anti-inflammatory properties at the molecular level. Innovative studies also suggest silymarin’s potential as a prebiotic, positively influencing gut microbiota composition, a key factor affected by obesity. These promising findings support the potential anti-obesity action of silymarin in clinical practice. Looking forward, using silymarin as an innovative complementary therapy could offer substantial benefits for natural health promotion and obesity management. Nevertheless, further research into optimal doses and cellular mechanisms is still needed.

1. Introduction

Over the last few decades, obesity has been considered a major health risk and received considerable attention from scientific circles. In this sense, the need for advances in the area of the prevention of obesity and its associated diseases has highlighted the search for integrative practices with anti-obesogenic potential [1].

Recent data reveal that developed countries with a high socioeconomic level are more likely to have healthy eating habits. However, in developing and underdeveloped countries, industrialized and ultra-processed food intake is still widespread [2,3]. Individuals of lower socioeconomic status often live in “food deserts”, areas lacking access to healthy food options. As per capita income declines, so does the availability of good-quality foods in these environments [4]. Furthermore, labor-saving technologies and the availability of electronic devices in household environments have greatly promoted a sedentary lifestyle [5], contributing to the installation and perpetuation of the obesity pandemic.

In this sense, it is known that obesity is well established as a disease with multifactorial etiology that involves genetic and environmental factors, favoring the development of other chronic non-communicable diseases such as metabolic syndrome, type 2 diabetes, cardiovascular diseases, and NASH (nonalcoholic steatohepatitis) [6]. These diseases represent the world’s leading cause of mortality [7]. Furthermore, obesity was an aggravating risk factor for mortality during the COVID-19 pandemic [8]. This high incidence of obesity, alongside the risk of metabolic disease onset, has instigated the growth of research over the last few decades on the cellular pathways involved in the pathophysiology of obesity and the search for possible effective interventions for its control [9].

Central to its etiology are intricate cellular mechanisms that govern energy homeostasis, lipid metabolism, and adipogenesis. At the core of these processes is the dysregulation of adipocytes, which are responsible for storing energy as lipids. Key pathways involved include the insulin signaling pathway, which, when impaired, leads to insulin resistance and altered glucose metabolism. Additionally, chronic inflammation driven by pro-inflammatory cytokines from adipose tissue contributes to the development of metabolic syndrome. The role of gut microbiota in modulating energy extraction and storage, along with genetic and epigenetic factors, further complicates the landscape of obesity. Understanding these cellular mechanisms is crucial for developing targeted therapies to combat this global health epidemic [10].

Throughout history, various methods have been explored in the quest for a lasting solution to obesity, ranging from ancient herbal medicines to cutting-edge pharmacological treatments. However, this journey has been marked by numerous obstacles. In the early 20th century, initial attempts to develop specific medications for obesity emerged, many of which relied on stimulant compounds like amphetamines to control appetite. Despite promising beginnings, these drugs often led to severe side effects and dependency issues, limiting their efficacy and safety [11].

In the 21st century, we are witnessing the rise of a new generation of anti-obesity medications that target metabolic and neuroendocrine pathways involved in weight regulation. Notable among these are melanocortin receptor agonists, serotonin and norepinephrine reuptake inhibitors, and (Glucagon-like Peptide-1) GLP-1 receptor agonists. However, despite advancements in research and development, these medications often face adverse effects, prescription limitations, and high costs, hampering their accessibility and acceptance among patients [12].

A holistic, integrative approach is essential in addressing the urgent need for personalized obesity treatments, integrating clinical, basic, and translational research for effective solutions. Recently, there has been a resurgence of interest in herbal medicine as an integrative approach to managing obesity and metabolic disorders [1]. Herbal medicine has been a longstanding tradition in diverse cultures worldwide. Medicinal plants harbor various bioactive compounds, like polyphenols, flavonoids, terpenes, and alkaloids, known for their health benefits. Many of these compounds have anti-inflammatory, antioxidant, antidiabetic, and lipid metabolism-regulating properties, which are crucial for obesity and related conditions [13].

Moreover, herbal medicine offers a holistic view, acknowledging the interconnectedness of the body’s systems and promoting overall health homeostasis. Unlike some pharmaceuticals, which target specific pathways, plant extracts often yield multiple therapeutic effects, addressing the complexity of obesity. For instance, extracts from plants like milk thistle (Silybum marianum (L.)) [14], green tea (Camellia sinensis (L.) Kuntze) [15], garcinia (Garcinia cambogia (L.) N.Ronson) [16], and turmeric (Curcuma longa L.) [17] have demonstrated potential in regulating body weight, reducing visceral fat, enhancing insulin sensitivity, and modulating lipid profiles.

In this sense, Silybum marianum (L.), commonly known as milk thistle, is a standout herb with a rich history in traditional medicine. Traditionally, it has been used to address various disorders, particularly those affecting the liver and gastrointestinal system. In recent years, scientific interest has turned to its key active compound, silymarin, for its potential in treating obesity and metabolic disorders [18].

Silymarin, a complex of flavonolignans, is the primary bioactive ingredient found in Silybum marianum (L.) Renowned for its antioxidant, anti-inflammatory, hepatoprotective, and antifibrogenic properties, silymarin has garnered attention. Recent research has unveiled numerous mechanisms through which silymarin may positively impact obesity and metabolic diseases [19]. Preclinical studies suggest silymarin could regulate lipid metabolism, enhance insulin sensitivity, mitigate inflammation, shield against oxidative stress, and modulate gut microbiota [20,21,22]. Moreover, clinical trials have shown promising outcomes regarding silymarin’s efficacy in reducing weight, improving lipid profiles, and managing blood glucose levels and gut microbiota in overweight and obesity [23,24,25]. These findings highlight the potential of Silybum marianum (L.) and its bioactive compound, silymarin, as a therapeutic agent in obesity and related metabolic disorders intervention.

Thus, this review aims to compile recent insights into the use of Silybum marianum (L.) and its bioactive compounds, including silymarin, for the treatment and prevention of comorbidities associated with obesity. Additionally, it will summarize the key cellular mechanisms underlying the anti-inflammatory, antioxidant, antidiabetic, and gut microbiota-modulating effects of this herbal medicine in the context of obesity. Thus, this review presents a novel perspective by providing a comprehensive overview and future outlook on the application of traditional herbal medicines like Silybum marianum (L.) in the management of modern metabolic diseases.

2. Obesity and Metabolic Diseases

Obesity is defined by a body mass index (BMI) equal to or greater than 30 kg/m² according to the World Health Organization (WHO) guidelines [26]. Obesity is associated with a series of health disruptions that can affect different systems, so it is crucial to understand the main related metabolic diseases. According to the WHO, in 2022, 1 in 8 individuals in the world experienced living with obesity. Even more worrying is the fact that worldwide adult obesity has more than doubled since 1990, and adolescent obesity has quadrupled over the same period [27]. Obesity has significant economic and social consequences that go beyond high medical costs. These indirect or social costs may include decreased quality of life and limited mobility, leading to mental health complications and making it difficult to participate in social activities, as well as difficulties with social adjustment, leading to problems with social interaction, social isolation, and discrimination [28]. It reflects an extremely worrying global trend and highlights the urge for comprehensive actions to combat this public health problem [27].

Overweight and obesity are significant risk factors for developing non-communicable diseases (NCDs) such as type 2 diabetes, marked by elevated fasting blood glucose levels (≥126 mg/dL) due to glucose intolerance, insulin resistance, or insufficient insulin production by the pancreas [29]. Additionally, overweight is closely tied to an increased probability of cardiovascular diseases, including hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, observed in multiple readings), favoring the risk of stroke, thrombosis, and heart failure. Obesity can also lead to dyslipidemia, characterized by abnormal bloodstream lipid levels (cholesterol and/or triglycerides), further elevating cardiovascular disease risk [30]. Also, high visceral adiposity leads to a state of insulin resistance, which can progress to hyperglycemia and type 2 diabetes [31]. The bidirectional relationship between obesity and type 2 diabetes creates a vicious cycle that exacerbates metabolic aggrievements [32]. Thus, nonalcoholic fatty liver disease (NAFLD), recently termed metabolic-associated fatty liver disease (MAFLD), is considered the hepatic manifestation of obesity and is characterized by excessive fat buildup in the liver in individuals with minimal alcohol intake [33]. This can lead to liver inflammation (NASH) and fibrosis (cirrhosis), with diagnosis confirmed through imaging tests such as abdominal ultrasound, often accompanied by changes in liver enzymes such as aspartate transaminase (AST) and alanine transaminase (ALT) into the bloodstream [34].

Furthermore, obesity can lead to metabolic syndrome, a set of metabolic risk factors that increase the chances of developing cardiovascular diseases and type 2 diabetes [35]. Metabolic syndrome is diagnosed based on clinical criteria established by the International Diabetes Federation (IDF) and adopted by the WHO, such as abdominal obesity (waist circumference > 102 cm in men and >88 cm in women); high blood pressure (>130/85 mmHg) or previous treatment for it; high triacylglycerols levels (>150 mg/dL) or previous treatment for it; low HDL-cholesterol levels (<40 mg/dL in men and <50 mg/dL in women) or previous treatment; and high fasting glycemia (>100 mg/dL) or previous diagnosis of type 2 diabetes. The presence of three or more of these criteria factors indicates the presence of metabolic syndrome [36].

Also, obesity is linked to respiratory disorders, including obstructive sleep apnea, which disrupts breathing during sleep, and asthma, caused by the pressure on the lungs due to an overload of weight and adipose tissue [37]. Additionally, obesity places extra stress on joints, potentially leading to long-term conditions like osteoarthritis, characterized by joint cartilage degeneration and chronic pain [38]. Moreover, recent studies have shown that obesity is associated with an increased risk of several cancers, including breast, colon, endometrial, kidney, and pancreatic cancer, among others [39].

Obesity has become a major public health concern in the 21st century due to its severity. Across the globe, we have observed an alarming increase in obesity rates over recent decades. According to the WHO, over 1.9 billion adults are overweight, with projections indicating that more than 890 million individuals have obesity (BMI ≥ 30 kg/m²) worldwide [27]. Cardiovascular diseases currently stand as the leading cause of death globally, with incidence rates varying based on factors like age, sex, race/ethnicity, and the presence of risk factors. However, it is estimated that over 17 million people succumb to cardiovascular diseases annually, constituting roughly 31% of all global deaths [40]. Hepatic steatosis, affecting roughly 25% of the world’s population, demonstrates higher prevalence rates in developed countries [41]. Type 2 diabetes affects over 400 million individuals worldwide, a number projected to exceed 600 million by 2045, according to the International Diabetes Federation [42]. Globally, in 2019, seven out of the top 10 causes of death were non-communicable diseases (NCDs). These seven causes constituted 44% of all recorded deaths or 80% of the top 10 causes. Collectively, NCDs represented 74% of global deaths in 2019 [43]. This overview provides insight into the epidemiological landscape of these NCDs. This surge is closely intertwined with modern lifestyles marked by high-calorie diets, sedentary habits, and environments conducive to obesity.

These epidemiological data show that metabolic NCDs associated with obesity have a major impact on health and are a central cause of mortality in contemporary society. This high prevalence of metabolic NCDs implies an overload to healthcare, with an economic impact on society and healthcare systems [44]. In light of this scenario, prioritizing preventive measures to curb the onset of these diseases within less primary healthcare has emerged as a key public health strategy to address the obesity epidemic. These preventive actions aim to improve society’s health while minimizing healthcare costs [45].

As an endocrine and metabolic disease, obesity affects the homeostasis of several cellular mechanisms [30]. Inflammation is a protective process crucial for maintaining homeostasis by acting as the initial response to infections and cellular repair [46]. However, many NCDs are associated with subclinical inflammation called metainflammation [47]. As obesity progresses, the lack of oxygen in adipose tissue leads adipocytes and resident macrophages to produce excessive amounts of pro-inflammatory cytokines [48]. This inflammation is sustained by ongoing activation of cellular pathways, such as the Toll-like receptor (TLR) pathway. TLR pathway triggers transcription factors like nuclear factor kappa B (NF-κB), which disrupts cytokine balance by increasing pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein 1 (MCP-1), while reducing anti-inflammatory cytokines like IL-10, IL-4, adiponectin, and the transcription factor PPAR-γ [49]. This TLR-driven inflammatory pathway contributes to several metabolic disorders, including type 2 diabetes, fatty liver disease, cardiovascular diseases, and certain cancers [35,50,51,52,53].

In obesity, metainflammation causes disruptions in insulin signaling due to the inefficient phosphorylation of serine and threonine residues on type 1 insulin receptor substrate (IRS-1). IRS-1 is crucial for transmitting signals from insulin receptors (IRs) to intracellular pathways such as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and extracellular signal-regulated kinases (ERKs)/mitogen-activated protein kinases (MAPKs), leading to insulin resistance [54]. Additionally, insulin resistance is linked to mitochondrial oxidative phosphorylation and oxidative stress [55,56,57,58]. A key aspect of mitochondrial metabolism involves the AMPK (AMP-activated protein kinase) pathway, regulating glucose uptake and β-oxidation [59]. AMPK influences the expression of various enzymes involved in insulin resistance like (insulin-regulated glucose transporter 4) GLUT4, and lipid metabolism like ACC (acetyl-CoA carboxylase) and CPT1 (carnitine palmitoyltransferase 1) [60,61] connecting energy balance at both cellular and whole-body levels.

Obesity leads to the production of oxidant molecules, such as superoxide from NADPH oxidases (nicotinamide adenine dinucleotide phosphate oxidase), and triggers processes like protein kinase C activation, oxidative phosphorylation, and glyceraldehyde oxidation [62]. Additional factors, including elevated leptin levels, weakened antioxidant defenses, and metainflammation, contribute to the generation of reactive oxygen species (ROS) and oxidative stress [30,63,64]. Low levels of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) combined with higher ROS and hydrogen peroxide (H₂O₂) production and increased NADPH oxidase activity [65,66,67] lead to the overproduction of redox-sensitive mRNAs such as NF-κB, MCP-1, IL-6, adiponectin, TNF-α, plasminogen activator inhibitor-1 (PAI-1), inducible nitric oxide synthase (iNOS), and interferon-γ (IFN-γ) [68,69]. Furthermore, ROS can lead to oxidative damage to mitochondrial DNA, favoring the onset of mitochondrial dysfunction [70]. Considering the complexity of the cellular mechanisms involved in obesity pathology and related metabolic diseases, it is noteworthy that interaction between inflammation, oxidative stress, and insulin signaling pathways play key roles in amplifying each other in obesity.

3. Silybum marianum (L.): An Overview

Silybum marianum (L.) Gaertn., popularly known as milk thistle, is an herbaceous plant with a rich and diverse history dating back around 2000 years [71]. Native to the Mediterranean regions, this plant belonging to the Asteraceae family has gained significant interest over the centuries due to its diverse medicinal properties and health benefits. Silybum marianum (L.) is an annual or biennial plant that grows spontaneously in several parts of the world, including Europe, the Americas, and Oceania [72]. Its distinctive features include dark green–white marbling leaves with prickly edges and vivid purple-to-pink flowers [73]. Besides its beauty aesthetic, this plant has been valued for its therapeutic and nutritional properties.

One of the most studied characteristics of Silybum marianum (L.) is the presence of bioactive compounds, especially flavonolignans, among which silymarin is the most outstanding. Recent research has highlighted the potential of this herbal medicine extract in treating and preventing liver diseases, including NAFLD, a condition that is becoming increasingly prevalent worldwide [74]. This substance is recognized for its hepatoprotective and cardioprotective properties [75], antioxidant [76], and anti-inflammatory [77] effects.

In addition to its liver health benefits, Silybum marianum (L.) is also considered a valuable dietary and herbal resource. Its medicinal properties have been explored in a variety of formulations, from dietary supplements to medicines for clinical use. The ease of cultivation of this plant makes it an accessible source of raw material for natural and herbal products. During the maturation process, the seeds accumulate flavonolignans, which are essential compounds in the formation of silymarin. The silymarin blend of polyphenolic flavonoids is mainly composed of silybin A and B, isosilibinin A and B, silydianin, silicristin, and taxifolin (Figure 1), silybins being the main constituents of silymarin [78,79]. These bio-asset substances are responsible for most of the therapeutic activity observed in Silybum marianum (L.) extract [80].

The chemical structure of silybins is composed of taxifolin and phenylpropanoid units linked to an oxerane ring structure. This molecular configuration gives silybins their hepatoprotective properties, helping to protect the liver from damage and promoting cell regeneration [19]. After oral administration, silybin undergoes extensive enterohepatic circulation, with an elimination half-life of approximately 6 h. About 3–8% is excreted unchanged in the urine, and 80% is eliminated in the bile as glucuronide and sulfate conjugates, with concentrations in bile 60–100 times greater than in serum. Approximately 20–40% of biliary silybin is recovered, while the remainder is excreted in feces. Silybin undergoes biotransformation in phases I and II in liver cells and interacts with a limited number of cytochromes (CYPs). In vitro studies suggest that silymarin extracts inhibit several CYP450, although they do not significantly influence CYP450 1A2, 2C9, 2D6, or 3A4/5. In addition to flavonolignans, studies have also identified other components in Silybum marianum (L.) extract, especially in milk thistle seed oil. Unsaturated fatty acids such as oleic acid (45.6%) and linoleic acid (29.0%) are present in significant quantities, along with minor compounds such as ethylbenzene and stearic acid. These compounds demonstrated antimicrobial activity against Gram-positive and Gram-negative bacteria, as well as antifungal [81], suggesting an interaction with gut microbiota modulation.

In the context of traditional medicine, Silybum marianum (L.) and silymarin (secondary metabolite) have been used for a variety of health conditions in addition to liver-related diseases. Its use ranges from treating gastrointestinal disorders to relieving skin illnesses and inflammatory diseases. This wide range of applications reflects the richness of bioactive compounds present in this plant.

4. Evidence of the Efficacy of Silybum marianum (L.) in Obesity and Metabolic Diseases

Obesity has a heterogeneous etiology, influenced by various factors, from genetic determinants to environmental and behavioral factors. Understanding this network of determinants is fundamental to developing effective approaches to obesity prevention and treatment, as it represents an important risk factor for several chronic comorbidities. The alarmingly increased incidence of obesity represents a crucial risk factor not only for cardiovascular diseases [82,83] but also for several other chronic non-communicable diseases, such as metabolic syndrome [84] and hyperlipidemia [83,85]. High visceral adiposity leads to insulin pathway disruption in a vicious cycle, positioning obesity as a primary risk factor for NAFLD, which can progress to steatohepatitis, liver fibrosis, and eventually, cirrhosis, significantly increasing the risk of liver failure and liver cancer [31,32,33].

Thus, the use of herbal medicines has grown as an alternative tool for obesity-related diseases, and this approach has gained increasing attention in the scientific community and among healthcare professionals. A promising example in this context is silymarin, an active compound extracted from Silybum marianum (L.) [86,87]. A 2021 preclinical study conducted by our group showed interesting results on the potential of silymarin in the prevention and treatment of comorbidities associated with obesity, as well as decreased body weight and body mass index of obese mice after 4 weeks of supplementation with a nutraceutical formulation with silymarin [88]. Another clinical study from our research group presented interesting results by showing the ability of silymarin associated with the nutraceutical compound to reduce anthropometric measurements such as mid-abdominal waist circumference, iliac crest waist circumference, waist-to-height ratio, and waist-to-hip ratio in volunteers with BMI ≤ 34.9 kg/m², after 180 days of supplementation [24].

Silymarin is recognized for its hepatoprotective, anti-inflammatory, and antioxidant properties [75,76,77]. In the context of obesity, research indicates that this herbal medicine may play an important role in the management of NAFLD [74], one of the main hepatic manifestations of obesity-related metabolic syndrome. Preclinical and clinical studies have suggested that silymarin can improve liver function, reduce inflammation and oxidative stress, and recover hepatic ectopic fat accumulation [24,88,89,90,91]. These beneficial effects may prevent the progression of NAFLD, avoiding the development of scalations, such as liver cirrhosis. Furthermore, silymarin has also demonstrated potential in aiding glycemic control and improving the lipid profile in individuals with obesity and type 2 diabetes [92]. Its antioxidant and anti-inflammatory effects may help modulate insulin resistance and dyslipidemia [93,94], cardiovascular risk factors commonly observed in this population. According to the study by Alsaggar et al. carried out in 2020, treatment with 50 mg/kg of silybin demonstrated several positive effects in obese mice that received a high-fat diet for 8 weeks, highlighting the reversal of adipose tissue inflammation and adipocyte hypertrophy. The study suggests that silybin may have an important role in controlling the inflammatory process and modulating adipose tissue metabolism, preventing excessive adiposity [95].

Moreover, a recent study on the 3T3-L1 adipocyte cell line demonstrated that silybin significantly reduced TNFα levels and increased glucose uptake, independent of GLUT4 protein expression after pro-inflammatory stimuli. This underscores silybin’s anti-inflammatory properties in an adipose tissue model, improving glucose intolerance present in obesity [96]. Silybin was able to inhibit weight gain and prevent the development of obesity, even without significantly affecting food intake rates. This suggests that its mechanisms of action extend beyond simple appetite control [95]. Also, a study on silymarin-loaded chitosan nanoparticles (SIL CH NPs) proposed mechanisms for weight loss by exploring their anti-hyperlipidemic and antihyperglycemic properties, which include enhanced HDL and testosterone levels. This natural compound exhibits promising effects in combating metabolic disorders that can lead to obesity. Additionally, these silymarin nanoparticles may help regulate the expression of neuropeptide Y (NPY) in the brain and serum cortisol, both key factors in appetite regulation [97]. Silybin also displayed reversal of fatty liver disease and restoration of glucose homeostasis, corroborating the potential of silybin in the management of NAFLD and in improving glycemic control, reversal of hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, overall factors strongly related to obesity. These beneficial metabolic effects demonstrate that silybin can improve the lipid profile and insulin sensitivity, which are fundamental aspects of metabolic syndrome associated with obesity. These findings reinforce the potential of silybin as a promising phytotherapeutic approach in the management of obesity and related conditions [95].

Cohort clinical studies investigating the use of silymarin demonstrate robust and promising results despite the limited data on obesity. The pharmacokinetics of silymarin flavonolignans, both single- and multiple-dose, were examined in patients with NAFLD or hepatitis C virus to determine whether silymarin’s disposition and potential efficacy vary among liver disease populations. Evidence of enterohepatic cycling of flavonolignans was observed only in NAFLD subjects. Therefore, the efficacy of silymarin may be more readily observed in NAFLD patients due to their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with hepatitis C virus patients [98]. A cohort study on dyslipidemia treatment compared a blend of nutraceuticals containing silymarin with atorvastatin, a standard drug treatment. Results indicated that the nutraceutical blend with silymarin was as effective as atorvastatin in lowering lipid levels, as evidenced by reductions in serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and cholesterol loading capacity. This blend also suppressed serum-mediated foam cell generation in human macrophages, acting as an antiatherogenic agent [99]. Additionally, a German real-world cohort study on NAFLD management in secondary and tertiary healthcare settings demonstrated that silymarin, as a co-medication, significantly contributed to NAFLD management in obesity and type 2 diabetes populations. Specifically, 17% of patients achieved a weight reduction of over 5% within one year of silymarin treatment. Similarly, an internet-based study focusing on lifestyle changes reported a weight loss of 10% in 15–20% of patients [100].

Silymarin significantly influences mitochondrial activity, which is often impaired in obesity. It enhances mitochondrial biogenesis and function by activating key cellular signaling pathways. One primary mechanism involves the activation of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a master regulator of mitochondrial biogenesis [21]. Silibinin increases PGC-1α expression, promoting the transcription of nuclear respiratory factors (NRF-1 and NRF-2) and mitochondrial transcription factor A (TFAM), which are crucial for mitochondrial DNA replication and gene expression [101]. Additionally, silymarin activates AMP-activated protein kinase (AMPK), a critical energy sensor that promotes mitochondrial biogenesis and fatty acid oxidation while inhibiting lipogenesis [102]. AMPK activation by silymarin enhances the expression of PGC-1α and its downstream targets, further supporting mitochondrial function and energy metabolism [103]. Silymarin also reduces oxidative stress by upregulating Nrf2, which induces the expression of antioxidant enzymes that protect mitochondrial integrity and function [101]. These mechanisms collectively improve mitochondrial efficiency, enhancing ATP production and reducing the accumulation of reactive oxygen species (ROS). By restoring mitochondrial function, silymarin aids in the regulation of energy metabolism and promotes the utilization of fatty acids for energy.

A recent study further corroborates the therapeutic potential of this phytochemical molecule. According to the results presented, treatment with capsules containing different doses of silybin (50 mg/kg and 100 mg/kg) for 8 weeks demonstrated the following effects in hamsters: protection against the development of fatty liver, indicating that silybin was able to prevent excessive fat accumulation in the liver [104]; reduction in lipogenesis, showing silybin ability to inhibit lipid synthesis, playing an important role in the regulation of hepatic metabolism [104]; and increased fatty acids oxidation, suggesting that silybin metabolic effect may stimulate the fatty acids oxidation as a source of energy, contributing to the improvement of the lipid serum profile and ultimately increased expression of phosphorylated AMPKα, which plays a central role in cellular energy metabolism [104]. The increased expression of phospho-AMPK indicates that silybin may act in the AMPK signaling pathway, modulating metabolism and energy homeostasis [104]. These results, along with the data previously presented, convincingly reinforce the therapeutic potential of silybin in the management of NAFLD, an important comorbidity associated with obesity. Silybin’s ability to modulate metabolic and inflammatory pathways relevant to this condition makes it a promising phytotherapeutic approach to explore.

According to Feng et al., obese mice that received oral administration of silymarin (30 mg/kg) for 1 month showed significant improvements in dyslipidemia, hepatic steatosis, and insulin resistance [20]. Furthermore, silymarin treatment increased the phosphorylation of AKT and FOXO1 (Forkhead box protein O1) and reduced the level of FOXO1 acetylation in cells with insulin resistance induced by palmitic acid, suggesting that silymarin acts by modulating intracellular signaling pathways related to insulin sensitivity. Results from molecular simulation and in vitro tests indicated that silymarin can directly bind to the sirtuin 1 (SIRT1) enzyme and increase its enzymatic activity [20]. Activation of SIRT1 may mediate the effects of silymarin in improving insulin resistance and gluconeogenesis, contributing to its antidiabetic activity. These findings further clarify the mechanisms of action by which silymarin exerts its beneficial effects in the context of obesity and its metabolic complications, such as dyslipidemia, NAFLD, and insulin resistance.

Another study investigated the impact of silybin (0.5 mg/kg/d) combined with a high-fat diet in a NASH-induced rat model, showing that silybin was shown to prevent visceral obesity and reduce visceral fat accumulation. Additionally, the research examined gene expression and observed that silybin treatment improved lipolysis by promoting the upregulation of adipose triglyceride lipase while inhibiting gluconeogenesis through the downregulation of genes such as FOXO1, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase [105].

The addition of 40 mg of silymarin for every 100 g of high-fat diet resulted in a loss of body weight in mice with diet-induced obesity, while food intake remained constant. Silymarin demonstrated a significant reduction in epididymal fat mass. The high plasma lipid levels in obese mice were all attenuated by silymarin, as well as insulin levels. Analysis of the cytokines TNF-α, IL-1β, and IL-6 showed that treatment with silymarin significantly reduces inflammation in obese mice [93].

Silymarin exerts profound effects on cellular signaling pathways associated with inflammation and oxidative stress, which are critical in the pathophysiology of obesity [1]. These anti-inflammatory and antioxidant effects of silymarin have a significant impact on energy metabolism and adiposity [106,107]. By reducing oxidative stress and inflammation, silymarin improves insulin sensitivity and enhances mitochondrial function, which leads to more efficient energy utilization and reduced adipogenesis [88,105]. Furthermore, the downregulation of NF-κB signaling helps to ameliorate chronic inflammation, a condition that disrupts metabolic homeostasis and promotes fat accumulation [21]. Consequently, the restoration of these pathways by silymarin not only alleviates oxidative and inflammatory stress but also contributes to the regulation of lipid metabolism, reduction in hepatic steatosis, and overall decrease in adiposity in individuals with obesity.

These pieces of evidence highlight the intrinsic relation of NAFLD and obesity-related metabolic disorders feedb-acking each other. In this context, silymarin and its byproducts stand out as a promising tool for obesity management, with evidence from in vitro, preclinical, and clinical models, building up a robust foundation of knowledge in this research field. Nevertheless, additional in-depth research is needed to better elucidate the unexplored facets of silymarin’s effects on health and disease.

5. Mechanisms of Action of Silybum marianum (L.) in Obesity and Metabolic Diseases

Silymarin and its derivatives may work in several pathways, including regenerating pancreatic beta cells, improving liver insulin sensitivity, reducing fat storage in adipocytes, and influencing key metabolic pathway enzymes. These effects are largely due to their confirmed antioxidative and anti-inflammatory properties. Consequently, silymarin may be a promising option for managing obesity and related metabolic diseases [108]. This topic will elucidate silymarin’s and its byproduct’s main known mechanisms of action as antioxidant, anti-inflammatory, and insulin sensitizer agents.

Silymarin can inhibit the activation of ERK1/2 (extracellular signal-regulated kinase 1/2) and prevent excessive activation of JNK1/2 (Jun N-terminal kinase 1/2. These central signaling pathways control numerous cellular processes such as proliferation, differentiation, survival, apoptosis, and stress response [109]. Silibinin treatment in an in vitro scenario also improved the expression of IL-10 by monocytes, a primary immune cell involved in obesity metainflammation onset [106]. Research suggests that silymarin is a strong inhibitor of NF-κB activation in response to TNFα. Silymarin prevents the NF-κBp65 subunit from moving into the nucleus without affecting its ability to bind to DNA) [107]. Additionally, silymarin inhibits NF-κB-dependent gene transcription and suppresses LPS-induced production of IL-1β and Cyclooxygenase 2 (COX-2) by blocking NF-κB [110]. Given NF-κB’s role in regulating proteins involved in the liver’s acute phase response, silymarin’s ability to inhibit NF-κB activation may contribute to its hepatoprotective effects. Preclinical and -clinical evidence has shown that silymarin exhibits anti-inflammatory effects by suppressing the release of cytokines such as TNF-α, IL-6, IL-1β, and IL-12β [80].

Also, silybin has been shown to decrease hepatic NF-κB activation by lowering the nuclear levels of the NF-κB p65 and p50 subunits and increasing the level of IκBα. It also reduces the levels of phospho-IκBα (NF-κB inhibitor alpha), which correlates with a decrease in IKK-α kinase (inhibitor of nuclear factor kappa B kinase subunit alpha) activity and consequently inhibits NF-κB DNA binding activity. Silybin can directly inhibit IKK-α kinase activity [107] without affecting TNFR1 (tumor necrosis factor receptor 1), TRADD (tumor necrosis factor receptor type 1-associated death domain protein), or RIP2 (receptor-interacting serine/threonine-protein kinase 2), indicating specific IκB kinase α inhibition. Furthermore, silibinin has been found to downregulate COX-2 expression [111]. Research suggests that silibinin effectively modulates cellular inflammatory responses by regulating the NF-κB pathway, reducing cytokine production such as IL-1β, IL-18, and TNF-α. This impact is attributed to IκB phosphorylate-on suppression, disrupting the transcription of inflammation-related genes [112,113]. Salamone et al. demonstrated that silibinin successfully modulates liver lipid homeostasis by actively inhibiting NF-κB activation [114]. Silibinin treatment also reduces Bcl-2 (B-cell leukemia/lymphoma 2 protein) levels by altering Bax levels (BCL2-Associated X, Apoptosis Regulator), which impacts the Bax/Bcl-2 ratio and ultimately leads to apoptosis [107]. The anti- and pro-apoptotic behavior of silymarin also considerably facilitates liver protection.

Milk thistle (Silybum marianum (L.)) derivatives such as silymarin, silibinin, or silybin have great antioxidant properties, neutralizing free radicals and boosting cellular antioxidant enzymes. Furthermore, silymarin provides hepatoprotective benefits by boosting antioxidant levels and increasing intracellular and liver glutathione while neutralizing free radicals [113]. It has been shown to decrease oxidative stress markers in hypercholesterolemia, demonstrating its antioxidant and chemoprotective effects on the liver due to its flavonolignans. Silymarin can enhance the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), as well as inhibit lipid peroxidation [71]. Utilizing exogenous natural antioxidants like silymarin can activate various antioxidant enzymes and stimulate non-enzymatic Nrf2 (nuclear factor erythroid 2-related factor 2) pathways, which in turn reduces oxidative stress [115]. Zhang et al. (2018) found that silybin can significantly hinder the activation of the NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome by increasing NAD⁺ levels. This increase supports the NAD⁺-dependent deacetylase sirtuin (SIRT2) and curbs the activation of the NLRP3 inflammasome, pointing to silybin’s potential for targeting the NAD⁺/SIRT2 pathway [116]. Elevated oxidative stress and the overproduction of pro-inflammatory cytokines can trigger apoptosis by activating the c-Jun NH2-terminal kinase (JNK) signaling pathway modulated by silymarin action [80]. Silybin also reduced superoxide anion release and normalized glutathione activity, and plasma lipid levels act against NASH-induced liver damage [117].

In recent years, silymarin has gained attention as a potential herbal medicine for diabetes. Clinical trials have demonstrated that silymarin can significantly lower fasting blood glucose, serum insulin, and glycated hemoglobin (HbA1c) levels [108]. Silymarin has a significant impact on HbA1c and insulin resistance through various mechanisms, such as providing antioxidant and anti-inflammatory effects, promoting β-cell regeneration, increasing insulin sensitivity, inhibiting gluconeogenesis, enhancing GLUT-4-mediated transport, and curbing NADPH oxidase activity [14]. Moreover, silymarin improves hepatic insulin resistance and gluconeogenesis in diabetic mice, with hepatic SIRT1 identified as a key target mediating these effects. FOXO1 activity is negatively regulated via a complex process involving increased fatty acid oxidation in the liver and SIRT1-mediated deacetylation and degradation of FOXO1 through the ubiquitin–proteasome pathway. This process directly influences hepatic glucose metabolism by affecting the transcription of key gluconeogenic proteins like G6Pase (glucose-6-phosphatase) and PEPCK (phosphoenolpyruvate carboxykinase) [20]. Nevertheless, a randomized, double-blind, placebo-controlled trial in type 2 diabetes patients did not observe any changes in insulin levels after administering 200 mg/day of silymarin for 4 months [118], suggesting more research is necessary in this area.

Silymarin has been shown to exert beneficial effects on the insulin receptor substrate 1 (IRS1)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, which is crucial for maintaining cellular glucose homeostasis and metabolic function. In obesity and metabolic syndrome, chronic inflammation and oxidative stress impair this signaling pathway, leading to insulin resistance [119]. Silymarin might exert its therapeutic effects by enhancing the phosphorylation of IRS1, facilitating its interaction with PI3K, thereby promoting the conversion of phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3). This conversion is pivotal for the activation of Akt, which subsequently phosphorylates downstream targets involved in glucose uptake and glycogen synthesis [120]. Silymarin’s antioxidant properties mitigate reactive oxygen species (ROS) levels, reducing oxidative stress and preventing the serine phosphorylation of IRS1, which is a key inhibitory modification in insulin signaling. Additionally, silymarin modulates the expression of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), further alleviating inflammation-induced disruptions in the IRS1/PI3K/Akt pathway [87].

Also, research investigating the effects of silibinin in a preclinical model of NAFLD subjected to silybin treatment demonstrated that silybin treatment improved insulin resistance, as evidenced by decreased Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index and enhancements in both the intraperitoneal glucose tolerance test (ipGTT) and the insulin tolerance test (ITT) [105]. Furthermore, silybin downregulated resistin levels and restored the functioning of the IRS-1/PI3K/Akt signaling pathway, highlighting its potential in ameliorating insulin resistance and metabolic dysregulation associated with NAFLD [121]. Silymarin also exerts significant regulatory effects on the Farnesoid X receptor (FXR) signaling pathway, which plays a crucial role in lipid and glucose metabolism, bile acid homeostasis, and inflammation [122]. In obesity, silymarin activates FXR, promoting the transcription of small heterodimer partner (SHP), which subsequently inhibits the expression of sterol regulatory element-binding protein 1c (SREBP-1c), a key regulator of lipogenesis [86]. This inhibition reduces lipid accumulation in the liver and adipose tissue, mitigating obesity-related complications. Moreover, silymarin-induced FXR activation enhances the expression of fibroblast growth factor 19 (FGF19), which improves glucose metabolism by increasing glycogen synthesis and decreasing gluconeogenesis in the liver. Additionally, FXR activation downregulates the inflammatory cytokines TNF-α and IL-6, reducing chronic inflammation commonly associated with metabolic syndrome [123].

A study examining silybin’s anti-obesity effects found that silybin increased the expression of insulin-induced gene 1 in a dose-dependent manner by interacting with sterol response element-binding protein (SREBP) cleavage. It also reduced lipogenesis in mature adipocytes and prevented differentiation in preadipocytes. SREBP1c can stimulate PPARγ by raising its expression and enhancing the production of an endogenous PPARγ ligand. PPARγ is a crucial transcription factor for genes involved in the initial stages of adipocyte differentiation and adipogenesis [14]. Silymarin greatly enhances the lipid profile and liver function and reduces oxidative stress in cases of fructose-induced NAFLD [124]. Oral administration of silymarin improves hepatic fatty acid metabolism by lowering mRNA levels of fatty acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP-1c), thereby boosting fatty acid synthesis and oxidation [80].

A study using a hypertriglyceridemic model found that silymarin can lower plasma triglyceride and cholesterol levels by boosting the protein expression of ATP-binding cassette (ABC) transporters and cytochrome P450 enzymes such as CYP7A1 and CYP4A. CYP4A plays a role in fatty acid hydroxylation, which is necessary for triglyceride synthesis, while both CYP7A1 and ABC transporters aid in cholesterol elimination and decrease overall cholesterol levels. ABC transporters like ABCG5 and ABCG8 facilitate cholesterol removal from hepatocytes to bile. Consequently, silymarin can raise HDL levels, which play a key role in the reverse transport of cholesterol [94].

Moreover, the administration of silymarin led to a significant decrease in cholesterol absorption, plasma cholesterol levels, and liver content of VLDL and triacylglycerol. The reduction in VLDL levels can be attributed to several factors, including decreased VLDL production and secretion from the liver, reduced VLDL secretion in the intestines, and inhibition of intestinal cholesterol absorption [125]. The study suggested that inhibiting enzymes like acyl-CoA cholesterol acyltransferase (ACAT), which plays a key role in lipid metabolism, could effectively reduce intestinal cholesterol absorption, particularly through phenolic compounds like silymarin [14].

Furthermore, parenteral administration of silymarin did not lower serum cholesterol levels in hypercholesterolemic rats, confirming the limited bioavailability of polyphenols in the gut lumen [123]. Another study examined the impact of different forms of silybin on lipid profiles and glucose metabolism in hereditary hypertriglyceridemic rats. The findings showed that silybin did not affect total cholesterol levels but significantly increased HDL-c levels and decreased serum triglyceride levels [14].

A clinical trial examining the use of silybin for 12 months found that it normalized transaminase levels (AST and ALT) and improved gamma-glutamyl transferase (γ-GT) levels and the degree of steatosis on ultrasonography, although these changes were not statistically significant. Additionally, the treatment was associated with improvements in fasting blood sugar, insulin levels, and HOMA-IR [91]. Silybin can lower cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme in cholesterol production [126]. This enzyme is also the target of cholesterol-lowering medications such as statins (lovastatin, simvastatin, and atorvastatin [127]. Moreover, silymarin can inhibit cholesterol absorption in the intestine [126]. Silymarin can help manage hyperlipidemia by decreasing liver triglyceride synthesis and promoting beta-oxidation of fatty acids in mitochondria [88,128].

Another important player in obesity pathophysiology is the gut microbiota. Most flavonoids have low bioavailability and, generally, do not reach the bloodstream. They are metabolized locally in the intestine, interacting with enterocytes and the gut microbiota. In this sense, it has been recently shown that flavonolignans, such as silymarin and its byproducts, might act as prebiotics metabolized by gut bacteria, serving as fuel for beneficial bacteria colony growth. Studies with formulations including silymarin, conducted by our research group, have shown microbiota modulation after silymarin supplementation associated with obesity-related metabolic improvements [22,25]. Also, silymarin has antibacterial and antifungal effects, inhibiting pathogenic microorganisms and promoting intestinal health and microbiota balance [81,129]. Moreover, recently, silymarin has been shown to stimulate the growth of specific bacterial B12 biosynthesis colonies, enriching the B12 vitamin apport and lowering the lipoproteins profile [130].

Silymarin decreases free radical production and lipid peroxidation and guards cell membranes from radical-induced harm by stimulating polymerase and RNA transcription. This herbal drug has antifibrotic properties, causes hepatic stellate cells to undergo apoptosis, promotes collagen breakdown, and reduces insulin resistance, fasting insulin levels, and levels of liver enzymes ALT and AST. Moreover, silymarin may contribute positively to the modulation of intestinal microbiota. Given the multitarget action of silymarin on various signaling pathways, Figure 2 offers a cohesive and instructional summary of its effects discussed in this topic. Furthermore, this glimpse of evidence suggests that combining silymarin with other treatments, particularly weight loss programs, can enhance its effectiveness [23].

The literature describes the direct interaction of silymarin and its bioassets with diverse cellular receptors. Silymarin displays antioxidant and reactive carbonyl-inducing properties, which can lead to the downregulation of p47phox protein expression, indicating that its antioxidant effects may involve direct interaction with p47phox [131]. Compounds within silymarin, such as silybin A and B, have shown effectiveness against SARS-CoV-2. These compounds can bind directly to human angiotensin-converting enzyme 2 (ACE2), preventing the virus from entering host cells, and they can also bind to viral proteins RdRp and helicase, thereby inhibiting viral replication and proliferation. Additionally, silymarin regulates the host immune response to indirectly suppress viral infection. Key immune regulation targets of silymarin include pro-inflammatory cytokines TNF-α and IL-6, along with growth factors like VEGFA (vascular endothelial growth factor A) and epidermal growth factor [132]. Additionally, silymarin compounds have been found to interact with several ATP-binding cassette transporters associated with anticancer and antiviral drug resistance. They may assist in modulating drug resistance by inhibiting multidrug resistance-associated proteins (MRPs) like MRP1-, MRP4-, and MRP5-mediated transport with high affinity. These compounds also significantly influence the ATPase activity of MRP1 and MRP4 without affecting [α-32P]8-azidoATP binding, suggesting that they interact primarily at the substrate-binding sites of the transporters [133]. Moreover, silymarin compounds exhibit significant antitumor effects in several cancer types, including lung, bladder, pancreas, liver, colon, skin melanoma, and hematological cancers. However, their impact on ovarian and breast cancer remains controversial due to silymarin’s selective estrogen receptor β (ER-β) agonist activity, which shows a strong binding affinity for ER-β and a milder affinity for ER-α. This estrogenic action demands caution in the context of female hormone-dependent tumors [134]. Nevertheless, it is noteworthy that most of these mechanisms might be influenced by obesity but are not involved in the onset of obesity pathophysiology, emphasizing the need for in-depth research on the interaction between obesity-related signaling molecules and the bioactive compounds of Silybum marianum (L.).

6. Contraindications and Drug Interaction of Silybum marianum (L.)

Silybum marianum (L.) and its secondary metabolites are recognized for their beneficial effects on metabolic homeostasis; however, it is crucial to understand when its use may be contraindicated. This section aims to provide essential insights for healthcare professionals and researchers in herbal medicine by thoroughly examining the contraindications associated with this medicinal plant.

One specific contraindication is the use of this herb during pregnancy and lactation. Despite extensive research on its benefits, evidence regarding its safety in these conditions remains limited [71]. Preclinical studies suggest that Silybum marianum (L.) might positively influence hormonal levels, potentially impacting fetal development and breast milk production [135]. However, clinical data on its use during pregnancy and lactation are lacking [136]. Therefore, healthcare professionals must carefully consider the potential benefits against the unknown risks during these critical periods. It is recommended to exercise caution and seek safer alternatives to ensure the health of both the mother and the fetus during pregnancy and lactation.

People with a history of hormonal neoplasia disorders, such as breast or uterine cancer, should avoid using this herbal medicine due to its effects on prolactin and estrogen pathways [134]. Animal studies indicate that Silybum marianum (L.) metabolites like silybin B, taxifolin, and quercetin may influence estrogenic activity by modulating Estrogen Receptor Beta (ERβ) [137]. In a preclinical study, the expected protective effect of dietary silymarin against breast carcinogenesis was contradicted by an increase in breast tumors, suggesting caution for breast cancer prevention [138]. In cases of breast cancer, where estrogenic action might be crucial, the potential interaction of this herbal medicine with hormonal levels is concerning. While some research indicates silymarin may protect against liver cancer and offer chemoprotective benefits, including mitigating the adverse effects of cancer drug therapy, there is a lack of clinical studies providing robust evidence on its safety in cancer patients [139]. Therefore, healthcare professionals should consider safer alternatives and therapeutic approaches for patients with hormonal neoplastic disorders, avoiding the potential risks associated with the indiscriminate use of milk thistle.

Allergic reactions to milk thistle, although rare, have been reported. Thus, people with a history of allergic reactions to plants in the botanical family Asteraceae, to which Silybum marianum (L.) belongs, should be monitored closely. Allergic reactions can manifest as rashes, itching, or swelling [140,141,142]. People with a history of gastrointestinal disorders should use this herbal medicine cautiously. While the plant is generally well tolerated, some people may experience gastrointestinal discomfort like nausea or vomiting [143,144]. Thus, despite its undeniable therapeutic benefits, its use might be contraindicated in some situations.

Milk thistle extract, known for its hepatic benefits, requires careful consideration of potential drug interactions [145]. To understand these interactions, it is important to understand how silymarin, the main bioactive compound in Silybum marianum (L.), is metabolized. Silymarin is primarily processed in the liver through the cytochrome P450 enzyme system, particularly by the CYP3A4 enzyme [146]. This pathway is significant because many other medications are also metabolized by the cytochrome P450 enzyme system, leading to potential drug interactions [147].

This interaction with the cytochrome P450 enzyme system can alter the metabolism of several medications, requiring careful monitoring, especially for patients on long-term treatment who are also taking Silybum marianum (L.). Using this herbal medicine alongside medications metabolized by cytochrome P450 can change their plasma concentrations, potentially increasing or decreasing their therapeutic effects [146]. Immunosuppressive drugs like cyclosporine and certain HIV antiretrovirals like ritonavir can be affected [148,149]. Another area of attention concerns anticoagulant medications, such as warfarin. Studies indicate that silymarin may have effects on the activity of warfarin, potentially increasing the risk of bleeding. This interaction occurs through the inhibition of CYP2C9, which is involved in warfarin metabolism [150]. Anticoagulant therapy should regularly monitor blood clotting times and adjust anticoagulant doses as necessary to avoid bleeding complications.

For people being treated for diabetes, using Silybum marianum (L.) concurrently may affect blood glucose levels [90]. Research shows that silymarin can have hypoglycemic effects, increasing insulin sensitivity and reducing plasma glucose [88]. Therefore, people with diabetes on hypoglycemic medications might need dosage adjustments when also using this herb to prevent episodes of hypoglycemia [90]. Additionally, some studies suggest that silymarin may interact with psychotropic medications, such as antidepressants and anxiolytics, influencing the metabolism of these substances by the hepatic enzyme system [151]. Although the exact mechanisms of these interactions are not fully understood, healthcare professionals should consider this possibility when prescribing silymarin to patients undergoing psychiatric treatment [152].

Thus, despite Silybum marianum’s (L.) undeniable therapeutic benefits, it might be contraindicated in some specific situations. Furthermore, this herbal medicine can interact with various medications, highlighting the importance of a cautious approach and continuous monitoring by prescribing professionals. To ensure therapeutic decisions are based on a comprehensive understanding of the patient, it is essential to individualize treatment, monitor frequently, and maintain open communication between healthcare professionals and patients. By understanding its contraindications, healthcare professionals can practice safely, maximizing the plant’s benefits while minimizing associated risks.

7. Conclusions and Future Directions

Obesity and metabolic diseases, such as type 2 diabetes, NAFLD, and metabolic syndrome, are increasingly prevalent and pose substantial public health challenges globally. Conventional treatment options for these conditions often include lifestyle modifications and pharmacotherapy. However, the search for more effective and safer therapeutic options continues, leading researchers to explore natural compounds like silymarin.

The literature and traditional therapeutic use of the milk thistle plant (Silybum marianum (L.)) and its active compound, silymarin, are extensive and widely acknowledged for its hepatoprotective potential. The liver, being a central organ in the pathophysiology of obesity, has brought attention to silymarin as a potential therapeutic agent for metabolic diseases beyond hepatic disorders. The data presented in this review demonstrate that silymarin’s action can impact other tissues crucial to the pathophysiology of obesity, including adipose tissue, as well as the endocrine and immune systems, in addition to its recently discovered interaction with the gut microbiota. Thus, silymarin has garnered significant attention for its potential therapeutic benefits in treating obesity and metabolic diseases. This interest stems from silymarin’s multifaceted biochemical properties, which include antioxidant, anti-inflammatory, and hepatoprotective effects. These attributes suggest that silymarin could play a beneficial role in managing conditions characterized by metabolic dysregulation. One of the key aspects of silymarin’s potential lies in its ability to modulate signaling pathways involved in metabolism. Studies discussed here have shown that silymarin can improve insulin sensitivity, reduce lipid accumulation in the liver, and enhance mitochondrial function. These effects are crucial because insulin resistance and hepatic steatosis are central features of metabolic diseases. By improving these parameters, silymarin may help mitigate some of the root causes of metabolic dysfunction.

Despite these promising findings, the exact mechanisms through which silymarin exerts its effects remain incompletely understood and might be considered a relevant study limitation. Investigations into the molecular mechanisms of silymarin’s action, including its specific molecular targets, remain limited and lack robust evidence from established obesity experimental models. Much of its positive effects are inferred from biological modulations during its medicinal use, highlighting the need for research employing refined methodologies to elucidate silymarin’s biological effects at the molecular level. This would enhance our understanding of this widely used hepatoprotective agent. Therefore, further in-depth studies are essential to fully characterize silymarin’s molecular interactions and therapeutic potential. Nevertheless, research indicates that silymarin may influence several molecular targets, including AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptors (PPARs), and nuclear factor kappa B (NF-κB). These targets are involved in energy balance, lipid metabolism, and inflammation, respectively. The modulation of these pathways by silymarin suggests a comprehensive approach to tackling metabolic dysregulation. Additionally, the bioavailability of silymarin poses another challenge. Silymarin is known to have poor absorption when taken orally, which may limit its therapeutic potential. Advances in formulation science are being explored to enhance its bioavailability and clinical efficacy.

However, before silymarin can be widely recommended as a treatment for obesity and metabolic diseases, several critical questions need to be addressed. One of the primary concerns is the long-term efficacy and safety of silymarin use. Most studies to date have been relatively short-term and conducted in animal models or small human trials. Large-scale, long-term clinical trials are necessary to confirm these initial findings and to establish dosing regimens that are both effective and safe for chronic use. Given the promising preliminary results, silymarin and Silybum marianum (L.) deserve continued scientific and clinical attention. The history of milk thistle application in traditional medicine, combined with its favorable safety profile, makes it an attractive candidate for further investigation. If future research confirms its benefits, silymarin could be integrated into current treatment paradigms for obesity and metabolic diseases, offering a natural, adjunctive therapy to complement existing approaches.