Sex Hormone: A Potential Target at Treating Female Metabolic Dysfunction-Associated Steatotic Liver Disease?

The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising due to rapid lifestyle changes. Although females may be less prone to MASLD than males, specific studies on MASLD in females should still be conducted. Previous research has shown that sex hormone levels are strongly linked to MASLD in females. By reviewing a large number of experimental and clinical studies, we summarized the pathophysiological mechanisms of estrogen, androgen, sex hormone-binding globulin, follicle-stimulating hormone, and prolactin involved in the development of MASLD. We also analyzed the role of these hormones in female MASLD patients with polycystic ovarian syndrome or menopause, and explored the potential of targeting sex hormones for the treatment of MASLD. We hope this will provide a reference for further exploration of mechanisms and treatments for female MASLD from the perspective of sex hormones.

metabolic dysfunction-associated steatotic liver disease, sex hormones, estrogen, androgen, sex hormone-binding globulin Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases and a leading cause of chronic liver disease. The threat posed by this condition to human health has drawn increasing attention.1 According to the latest report, which includes data from nearly 60,000 individuals, the overall prevalence of the disease is 29.38%.2. In 2020, metabolic dysfunction-associated fatty liver disease (MAFLD) was introduced as an updated version of NAFLD, with simpler and more accessible diagnostic criteria.3 In June 2023, NAFLD was renamed again, and the term metabolic dysfunction-associated steatotic liver disease (MASLD) was introduced by three major liver transnational associations. This term includes patients with hepatic steatosis and at least one cardiometabolic risk factor, without the need to exclude other liver diseases such as viral hepatitis or excessive alcohol consumption. MASLD emphasizes the role of insulin resistance (IR), dyslipidemia, and type 2 diabetes mellitus (T2DM), and has now been widely adopted in many countries.4 Although liver biopsy is considered the “gold standard” for diagnosing MASLD, it is not practical for widespread population screening. In contrast, imaging tests, risk scores, and biomarkers such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are commonly used in clinical practice to assess and monitor disease progression.5 MASLD encompasses a range of liver disorders, from simple fat accumulation to the more severe metabolic dysfunction-associated steatohepatitis (MASH). MASH can progress to significant fibrosis and cirrhosis, and in some patients, persistent inflammation in the liver parenchyma may lead to cirrhosis advancing to hepatocellular carcinoma (HCC).6, 7, 8 MASH has become increasingly common as an indication for liver transplantation and is now the second most common reason for transplantation in the United States, following alcohol-related liver disease.9 Therefore, it is crucial to prevent MASLD by exploring its underlying pathophysiological mechanisms. The original theory of the pathogenesis of MASLD and MASH was the “two-hit hypothesis”.7 The “first hit” leads to increased liver lipid deposition and steatosis when fat accumulation in the liver exceeds 5%, while the “second hit” triggers fibrogenesis.10 However, this early theory has become outdated due to its overly simplistic definition. Today, the “multiple-hit hypothesis” is widely accepted, suggesting that IR, hormone levels secreted by adipose tissue, changes in the gut microbiome, nutritional factors, and genetic factors more accurately explain the pathogenesis of MASLD.11 Previous studies have indicated that males (40%) are more affected by MASLD than females (26%).12 However, compared with premenopausal women, the prevalence of MASLD significantly increases in postmenopausal women, peaking between ages 60 and 69 and declining after age 70.13 This striking sex difference and change in incidence suggest that aging is not the primary cause of MASLD development in women, but rather changes in sex hormone levels may play a key role. Numerous studies, including animal models and clinical trials, support the relationship between reduced estrogen levels and hepatic steatosis, which is the most evident change in MASLD.14, 15, 16, 17 Elevated androgen levels have also been shown to be related to MASLD.18,19. Additionally, some studies have highlighted the roles of sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and prolactin (PRL) in MASLD, revealing the related mechanisms.20, 21, 22, 23 Moreover, in the absence of an effective remedy for MASLD, several studies have suggested that sex hormones and their receptors may play an important role in developing therapeutic agents.24,25 Therefore, this article aimed to review the role and application of female sex hormones in MASLD and explore the underlying pathophysiological mechanisms. We hope this will provide new insights and therapeutic approaches to alleviate the burden of MASLD for more people. Search Strategy PubMed was searched electronically to collect the published literature reporting the effects of sex hormones on female MASLD. The search covered studies from the inception of the database to May 2024. The search terms and formula were as follows: the abstract included (sex hormone or estrogen or androgen or sex hormone-binding globulin or follicle-stimulating hormone or prolactin or polycystic ovary syndrome or menopause) and (metabolic dysfunction-associated steatotic liver disease or non-alcoholic fatty liver disease or metabolic (dysfunction)-associated fatty liver disease or metabolic dysfunction-associated steatohepatitis or non-alcoholic steatohepatitis or liver or fibrosis or steatosis or lipogenesis or adipogenesis). The limits applied were female and English language. THE EFFECT AND MECHANISM OF SEX HORMONES IN THE DEVELOPMENT OF MASLD Estrogen 17β-Estradiol (E2) is the primary estrogen, mainly synthesized by the follicular membrane and granulosa cells of the ovaries before menopause.26 E2 exerts its effects through estrogen receptors (ERs), which primarily consist of ERα, ERβ, and the recently discovered transmembrane G protein-coupled estrogen receptor (GPER) on the cell membrane.27 ERα is the most abundant subtype, while ERβ and GPER are expressed in lower quantities.28 Both ERβ and GPER are present only in hepatic stellate cells (HSCs), where ERα is not expressed.28, 29, 30, 31 Therefore, most studies support the involvement of classical ERα32,33 in the primary mechanism of liver lipid metabolism as demonstrated by ERα gene knockout studies in mice. Sara Della Torre et al. demonstrated that estrogen and ERα are essential for reducing lipid deposition in the liver using a liver-specific ERα mouse model.34 Similarly, Pedram et al. found that using propyl-pyrazole-triol (PPT), an ERα agonist, effectively improved hepatic steatosis in both wild-type mice and mice that only expressed ERα at the membrane. However, this result was not observed in ERα knockout mice.35 Despite these findings, a few studies using the same method suggested that ERα may not be responsible for reducing hepatic lipid accumulation.32,36 It is now widely accepted that estrogen is a protective factor in the progression of MASLD. Nemoto Y et al. first observed that estrogen deficiency in mice with aromatase deficiency led to substantial lipid droplet accumulation in liver cells, indicating hepatic steatosis. However, E2 supplementation successfully prevented hepatic steatosis in aromatase-deficient mice, suggesting that estrogen plays a key role in preventing MASLD.14 With the recent emergence of hot spots in estrogen research, a large number of progression. Recent clinical trials focusing on postmenopausal women and individuals with Turner syndrome, who have low estrogen levels, further support the protective role of estrogen as these groups experience increased MASLD incidence.13,37,38 The formation of excessive liver triglycerides (TGs) in MASLD patients results from an imbalance between increased lipid uptake and de novo lipogenesis (DNL) in the liver.39 Early studies suggested that estrogen signaling in females might inhibit gene expression related to liver DNL, such as sterol regulatory element-binding transcription factor 1c (SREBP1c),40 which significantly enhances cholesterol and TG production. Estrogen deficiency in ovariectomized mice led to hepatic IR, increased DNL and fatty acid input, and promoted MASLD development.39,42,43 Additionally, E2 has been shown to inhibit the expression of hepatic fatty acid synthase and stearoyl-CoA desaturase 1 (SCD1), both of which are critical mediators in maintaining liver lipid homeostasis.44 These findings suggest that estrogen is indispensable in alleviating liver lipid deposition. In addition to improving fatty liver, estrogen also plays a significant role in inhibiting liver fibrosis mechanisms. Upon activation, HSCs transform into myofibroblast-like cells, characterized by proliferation and α-smooth muscle actin (α-SMA) expression, along with the synthesis of extracellular matrix components such as type I, Ⅲ, and Ⅳ collagen, which form the core stage of liver fibrosis.45 Studies using rat models of dimethylnitrosamine-induced liver fibrosis have shown that estradiol effectively prevents type I collagen formation, inhibits α-SMA expression, and reduces excessive cell proliferation. Estradiol intervention slowed HSC proliferative activity and lowered mRNA levels of type I and Ⅲ procollagens in the liver.46 Recently, increasing research has focused on the signaling pathways and molecular mechanisms by which estrogen influences the pathogenesis of MASLD. These include the adenosine monophosphate-activated protein kinase (AMPK) pathway, c-Jun N-terminal kinase (JNK) pathway, peroxisome proliferator-activated receptor α (PPARα), and peroxisome proliferator-activated receptor γ coactivator 1 (PGC1), which we have reviewed and described below. AMPK Laia Vila et al. conducted an experiment in which rats were fed fructose, but only female rats exhibited a significant increase in fructokinase. It led to a substantial rise in the adenosine 5′-monophosphate (AMP)/adenosine 5′-triphosphate (ATP) ratio and protein kinase activation. AMP is a critical substrate for AMPK activation,47 indicating that the AMPK pathway may play a role in the mechanism through which estrogen regulates hepatic lipid metabolism. AMPK is a kinase composed of three different subunits. When activated, it can inhibit ATP consumption and promote ATP production, leading to reduced liver lipogenesis and increased fatty acid oxidation.48 AMPK has been shown to mediate membrane ERα signaling transduction. On one hand, AMPK can regulate the effect of estrogen on reducing adipogenesis and promoting fatty acid oxidation by maintaining the phosphorylation of acetyl-CoA carboxylase (ACC), a key enzyme in lipid production.49,50 On the other hand, studies have found that an ERα agonist, PPT, can activate both AMPK and extracellular signal-regulated kinase (ERK), thereby inhibiting the production of SREBP1. Liver-specific overexpression of SREBP1 is known to increase the expression of lipid synthesis genes and significantly enhance cholesterol and TG production.35,41 These findings suggest that AMPK mediates estrogen’s effects in treating MASLD, and ERα agonists such as PPT hold promise in reducing hepatic fat accumulation. JNK JNK is part of the mitogen-activated protein kinases (MAPKs) signaling pathway, and its sustained activation is critical in liver injury.51,52 Phosphorylated JNK (phospho-JNK) can bind to proteins in the mitochondrial outer membrane, forming SH3 domain-binding protein 5 (Sab). This interaction initiates signaling transduction in mitochondria, damaging the respiratory and electron transport chains and leading to the release of mitochondrial reactive oxygen species (ROS), which can mediate apoptosis or necrosis.53 Studies have shown that primary hepatocytes from female mice exhibit stronger resistance to JNK-dependent acetaminophen-induced acute liver injury compared with their male counterparts, with significantly reduced expression of liver Sab protein.54,55 Win et al. found that the level of Sab protein in the mitochondria of female mice was 20% lower than in male mice. It suggests that estrogen (specifically, E2) contributes to protective mechanisms against liver damage induced by acetaminophen by suppressing Sab protein levels. E2 can increase the expression of tumor protein p53 (p53), which induces the expression of miR34a-5p that targets the coding region of Sab mRNA, reducing Sab protein levels, leading to the inhibition of JNK-sustained activation, thereby mitigating damage to the respiratory and electron transport chains and reducing ROS release, ultimately alleviating liver injury. Similar results have been observed in premenopausal women, who demonstrate increased levels of liver p53 and lower levels of Sab compared with age-matched men. However, postmenopausal women show no difference in Sab expression compared with men.56 The precise role of estrogens in this pathway remains unclear, and further experimental studies are needed to achieve a comprehensive understanding. PPARα PPARα is a key nuclear receptor in the liver that regulates energy homeostasis by controlling β-oxidation, fatty acid transport, and ketone body formation.57 Studies have shown that liver steatohepatitis is exacerbated in PPARα-deficient mice subjected to high-fat diets.58 In MASH patients, reduced liver expression of PPARα is observed alongside impaired mitochondrial function and increased oxidative stress in the liver.59,60 In thioacetamide-induced rat liver fibrosis, PPARα helps reduce the pool of ROS by detoxifying hydrogen peroxide and upregulating catalase expression and activity, thereby improving oxidative stress and protecting liver function.61 Additionally, the PPARα agonist Wy-14,643, which pharmacologically activates PPARα, has demonstrated both prophylactic and therapeutic effects against MASH in mice.62,63 However, an animal experiment conducted by Morise et al. revealed that a saturated fatty acid diet induced hepatic lipid accumulation in both female and male mice. Notably, female mice exhibited comparably lower liver TG content, although their plasma TG levels were higher than those of male mice. This gender difference is attributed to mild downregulation of PPARα and higher expression of ERs in the liver tissues of female mice compared with males. The relatively lower hepatic TG storage in female mice may be due to increased secretion of TG from the liver into plasma, which PPARα regulates through fatty acid oxidation.64 Tamoxifen, a non-steroidal tristyrene anti-estrogen drug commonly used as adjunct therapy for breast cancer,65,66 has been associated with the development of fatty liver and steatohepatitis in treated patients.67,68 A potent PPARα agonist known as bezafibrate has shown efficacy in improving hepatic steatosis in breast cancer patients undergoing tamoxifen treatment by activating peroxisomal oxidation.69 However, the effect of PPARα agonists appears to be diminished in younger female mice on high-fat diets compared with their male counterparts. Another PPARα agonist, fenofibrate, while exhibiting similar effects on hepatic PPARα expression in both genders, was less effective in elevating the expression of PPARα target genes encoding enzymes for fatty acid β-oxidation in female mice than in male mice.70 This suggests a signaling cross-talk between peroxisome proliferator-activated receptor (PPAR) and ER. Previous studies have demonstrated that the PPAR/retinoid X receptor complex can interact with ER, inhibiting transactivation by competing for the estrogen response element.71 Further research is needed to explore the sex differences in the response to fatty liver-targeted therapies, aiming to develop appropriate therapeutic regimens for clinical practice. PGC1 Mitochondria serve as the central hub for metabolic activity, making them the primary site for fatty acid oxidation. Consequently, mitochondrial quality control targeting hepatocytes for MASLD treatment has become a research hotspot.72 A crucial aspect of mitochondrial quality control is mitochondrial biogenesis, regulated by the PGC1s, including PGC1α and PGC1β. In the liver of female mice, PGC1s are highly expressed, which is required for managing oxidative stress and is found to be estrogen-dependent.73 Conversely, specific reduction of PGC1α in the liver results in decreased fatty acid oxidation and increased hepatic IR, both recognized as primary characteristics of MASLD.74 The PGC1 family of transcription coactivators plays a vital role in processes such as adipogenesis, liver gluconeogenesis, and fatty acid oxidation by interacting with various transcription factors.75,76 Research in rats has shown that overexpression of PGC1α can significantly decrease hepatic TG accumulation, both in vivo and in vitro.77 PGC1β also plays a vital role in regulating the function of mitochondria and defending against oxidation.75,78 Notably, its overexpression has been linked to HCC development. In female mice, PGC1β can compensate for oxidative stress when PGC1α is completely absent,73 highlighting its importance in maintaining mitochondrial health. These findings underscored the need for further studies to explore the impact of estrogen on liver mitochondrial dynamics in patients with MASLD. The molecular mechanisms by which estrogen influences the pathogenesis of MASLD are described below and summarized in Figure 1. Androgen Females generally have lower levels of androgens compared with males,79 primarily consisting of testosterone produced by the ovaries, dehydroepiandrosterone (DHEA), and androstenedione (A4) produced by the adrenal glands. A cross-sectional study has indicated that serum levels of total testosterone, free testosterone, DHEA sulfate, and androstenedione may decrease with age in females.80 However, a growing body of research suggests a correlation between hyperandrogenism in females and the onset of fatty liver disease and liver fibrosis. Kanaya et al. observed a significant increase in lipid deposition in the liver of ovariectomized female mice administered dihydrotestosterone (DHT), a non-aromatic androgen.81 A meta-analysis conducted by Jaruvongvanich et al. demonstrated a gender difference regarding serum total testosterone levels and MASLD, indicating that elevated total testosterone levels increase the risk of MASLD in women but not in men.19 Similarly, Sarkar et al. investigated 1052 premenopausal women and found a notable correlation between testosterone levels and MASLD in females.82 Many studies suggest that the link between elevated testosterone and MASLD may be related to IR. Jee-Young Oh et al. demonstrated a significant positive correlation between bioavailable testosterone and insulin levels in women, suggesting that hyperandrogenism is linked with IR.19 Furthermore, research has shown that high testosterone levels are linked to increased visceral adipose tissue and decreased skeletal muscle mass.83 Spironolactone, a competitive antagonist of specific androgen receptors (ARs), has been shown to treat symptoms of hyperandrogenemia in polycystic ovarian syndrome (PCOS) patients and may help prevent MASLD in women.84,85 Recent evidence indicates that testosterone can heighten the risk of MASLD irrespective of obesity and IR.18 The binding of testosterone to AR facilitates the entry of the ligand into the nucleus, leading to AR signaling transduction through genomic and rapid non-genomic actions. In the genomic pathway, the androgen-AR complex binds as a dimer to androgen response elements in the promoters of target genes, promoting their transcription.86,87 The non-genomic pathway primarily involves the MAPK/ERK signaling pathway. In addition to these pathways, other molecules and signaling pathways have been explored regarding how androgens promote female liver steatosis. These include nuclear factor kappa B (NF-κB), branched-chain amino acids (BCAA), and SREBP1c. We reviewed and described them as follows. NF-κB Cui et al. used DHT-exposed rats to model female patients with PCOS who exhibit hyperandrogenemia. Their findings indicated the activation of the NF-κB signaling pathway, accompanied by increased levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and other inflammation-related markers. Moreover, there was a significant rise in biochemical markers such as AST, ALT, and high-sensitivity C-reactive protein (hs-CRP), suggesting the establishment of a chronic low-grade inflammatory state characteristic of metabolic dysfunction-associated MASLD.88,89 NF-κB has been implicated in liver tissue injury and fibrosis. It plays an essential role in the progression of hepatic fibrosis through three distinct pathways: first, by modulating inflammatory signaling pathways associated with macrophages and other inflammatory cells in the liver; second, by regulating the initial injury to liver cells that triggers fibrosis; and third, by influencing the fibrotic response of HSCs.90 Notably, the activation of NF-κB occurs predominantly in HSCs or hepatic myofibroblasts (HmFs), with minimal activation observed in hepatocytes.91 BCAA Alvaro Anzai et al. conducted a study in which they treated 2-day-old female rats with neonatal T and observed a greater accumulation of lipid droplets in the liver as the rats reached adulthood. The testosterone-treated rats exhibited increased concentrations of BCAA and decreased activity of liver fatty acid elongase 2.92 Some intermediates formed during the catabolic process of excess BCAA may be toxic to the body.93 Previous studies have established a relationship between elevated circulating BCAA levels and increased IR. BCAAs activate mechanistic target of rapamycin complex 1 signaling, which leads to serine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2, thereby exacerbating IR.94 Additionally, decreased catabolic activity of BCAAs is inversely correlated with circulating BCAA levels and hepatic lipid accumulation.95 Based on these findings, we speculate that there may be a connection between androgen levels and fatty liver through the modulation of BCAA metabolism. SREBP1 Tina Seidu et al. induced female mice with a low dose of DHT and demonstrated that DHT increases DNL proteins by regulating SREBP1, leading to increased hepatic lipid accumulation.96 SREBP1 is involved in the DNL process and is the main regulator of adipogenesis.97 The process of SREBPs traversing the endoplasmic reticulum membrane involves the proteolytic activation of their N-terminal domains, which are distributed from the membrane. Subsequently, they are transported to the nucleus, where they trigger the activation of genes responsible for regulating lipid metabolism.98 Sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and sterol levels have been found to control this proteolytic process.99 Compared with the control group, SCAP expression, SCAP-SREBP1 binding, and SCAP mRNA were increased in DHT mice. The binding amount of AR and SCAP intron 8 in DHT mice was nearly eight times higher than that of control mice. This suggests a vital role of AR and SCAP intron 8 binding in regulating the levels of SCAP and SREBP1 mRNA and protein.96 SHBG SHBG, a glycoprotein predominantly synthesized in the liver, has a strong affinity for various sex steroids, particularly testosterone, and plays a crucial role in transporting these hormones via plasma to their target tissues.100 Multiple clinical studies have indicated that low levels of SHBG are significantly associated with metabolic syndrome 101and T2DM.102 Obese individuals exhibit lower plasma SHBG levels than those of normal weight,103 and obesity is considered one of the primary risk factors for MASLD.104,105 According to a meta-analysis, subjects with MASLD have lower SHBG levels compared with those without MASLD in both sexes. Further sex-stratified analysis revealed a more significant negative correlation between SHBG levels and disease occurrence in female MASLD patients compared with males.19 Moreover, SHBG may serve as a prediagnostic risk marker for clinical assessment of HCC risk in patients.106 The connection between SHBG and MASLD remains unclear. Pomme I.H.G. Simons et al. investigated the relationship between stable isotopically measured DNL and serum SHBG in a cross-sectional study. Their results indicated that DNL is involved in the regulation of SHBG, showing a negative correlation between female DNL and SHBG.107 Previous animal and in vitro studies have demonstrated that a saturated fatty acid, palmitate—the main end-product of DNL—directly reduces the expression of SHBG in HepG2 cells.108 Furthermore, hepatocyte nuclear factor-4α (HNF-4α), ERα, and PPARγ have been shown to competitively bind to SHBG promoters. While HNF-4α stimulates SHBG promoter activity to increase SHBG expression, peroxisome proliferator-activated receptor gamma inhibits SHBG expression.109 DNL can lead to the downregulation of HNF-4α expression, resulting in decreased SHBG expression.108 Cytokine dysregulation is a significant factor in MASLD, as certain proinflammatory cytokines may stimulate SHBG production, while anti-inflammatory cytokines may reduce it. Maintaining a balance between these cytokines is crucial for properly regulating SHBG and preventing MASLD development.109 TNF-α and IL-1β promote hepatic steatosis and fibrosis. Through activation of the NF-κB signaling pathway, TNF-α decreases mRNA and protein expression of HNF-4α in HepG2 cells, significantly inhibiting SHBG production.110,111 Administering IL-1β daily to human SHBG transgenic mice resulted in a notable reduction of plasma SHBG and liver SHBG mRNA levels, which is also linked to downregulation of HNF-4α.112 Adiponectin, a hormone released by adipose tissue, plays a crucial role in secreting various endocrine factors.113 Recent studies have shown a close correlation between liver disease and adiponectin receptors 1 and 2.114 In vivo studies indicate an association between low serum adiponectin levels and MASLD.115 Simo et al. demonstrated that adiponectin levels are positively associated with both HNF-4α and SHBG mRNA levels through in vitro studies of HepG2 cells and human liver biopsies.116 Adiponectin treatment induces changes in liver enzyme activity via activation of AMP-activated protein kinase, resulting in a reduction in liver TG content and free fatty acids, which subsequently increases HNF-4α levels.116 Recent studies suggest that SHBG itself may be closely related to MASLD. An investigation of individuals at high risk for T2DM revealed that liver fat mass is the strongest predictor of SHBG levels.117 High carbohydrate diets increase liver lipogenesis, leading to a decrease in liver SHBG production.108 This indicates that fat content in the liver is negatively correlated with serum SHBG.17 Additionally, studies have shown that SHBG levels are positively correlated with high-density lipoprotein and negatively correlated with TGs118 Beyond serving as a biomarker for MASLD, the downregulation of SHBG has also been linked to the pathogenesis of MASLD. A recent study provided experimental evidence that SHBG prevents the progression of MASLD by downregulating lipogenesis. Cristina Sáez-López et al. collected liver samples from MASLD patients for analysis and found that the expression level of SHBG mRNA was negatively correlated with liver TG content and ACC mRNA levels.20 It is well-known that one feature of MASLD is increased liver TGs due to DNL, while ACC is a key enzyme in liver fat production.119 In HepG2 cells, overexpression of SHBG downregulates the levels of ACC mRNA and protein under both basal and high glucose conditions.20,120 The results suggest that overexpression of SHBG in HepG2 cells blocks the increased levels of ACC genes in high glucose culture conditions.20 These findings offered a new perspective on therapeutic approaches for MASLD and indicated that increasing SHBG expression might be a promising therapeutic strategy with significant clinical application value. FSH FSH is also believed to impact the pathogenesis of MASLD. However, their specific roles in this process remain controversial and unclear, necessitating further experimental research to analyze their mechanisms of action. FSH is an indispensable component of the hypothalamic-pituitary-gonadal axis. As the main hormone secreted by the anterior pituitary gland, it functions through its specific membrane receptor, known as the FSH receptor (FSHR), which regulates the synthesis and secretion of gonadal hormones.121,122 Studies have shown that FSH can affect organs and tissues beyond the reproductive system. An epidemiological survey conducted among 1635 women aged 55–89 years in East China identified a correlation between FSH and MASLD for the first time.23 The results suggested a negative correlation between FSH levels and the homeostasis model assessment of insulin resistance. After adjusting for covariates, this correlation weakened but persisted, indicating that it was unlikely due to chance and that IR may play a role in how FSH can improve female fatty liver after menopause. Furthermore, this study revealed that luteinizing hormone (LH) did not show a significant correlation with hepatic steatosis in any of the models, supporting the assumption that LH is not a principal factor in the progression of MASLD.23 Some studies have suggested that FSH and FSHR may be involved in regulating lipid metabolism. Liu et al. used a polyclonal antibody against the FSH beta subunit to block the FSH-FSHR connection, finding that total, subcutaneous, and visceral fat volumes were significantly reduced in mice treated with these antibodies. They believe this result is related to antibody-induced adipocyte beiging.123 Beige adipocytes, which are transformed from white adipocytes under the influence of exercise and cold, share functions with brown adipocytes. Beige adipose tissue has been shown to participate in glycolipid metabolism and may offer a potential treatment for obesity and T2DM.124, 125, 126 The beiging of adipocytes is accompanied by a marked increase in uncoupling protein-1 (UCP-1) levels, as the thermogenic function of mitochondria relies on UCP-1 gene expression.127 Therefore, we speculate that FSH may reduce the beiging of adipose tissue by inhibiting UCP-1 expression, which could decrease mitochondrial biosynthesis and lead to fat accumulation. Additionally, Cui et al. administered FSH to differentiating avian preadipocytes and found that it significantly promoted the accumulation of intracellular lipids, with a significant upregulation of FSHR mRNA. In vivo experiments with abdominal fat tissue corroborated these findings, suggesting that acyl-CoA synthetase is involved in this process. FSH upregulates the expression of Acsl3, a key gene in lipid synthesis,128 which activates fatty acids to form acyl-coenzyme A (acyl-CoA), the first step in long-chain fatty acid metabolism.129 Yang Song et al. reported a positive correlation between serum FSH and low-density lipoprotein cholesterol (LDL-C) levels in postmenopausal women aged 42–60 years who underwent hormone replacement therapy (HRT). This was attributed to an FSHR-mediated decrease in LDL receptor expression and LDL-C degradation in liver tissue.130 However, elevated LDL-C has been established as a risk factor for female MASLD.131 The discrepancies in the outcomes of these clinical studies may relate to the different ages of the subjects included. In addition, Guo et al. identified FSHR expression in the liver and found that FSH influences total cholesterol metabolism by regulating liver cholesterol biosynthesis. Through clinical trials, they first discovered that perimenopausal women exhibited elevated FSH levels and a significantly increased prevalence of hypercholesterolemia. In animal experiments, when exogenous FSH was administered to ovariectomized mice that had eliminated the effects of E2, they observed that FSH increased cholesterol levels by upregulating the rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), involved in cholesterol biosynthesis. By further exploring the mechanism, they found that SREBP-2/FoxO1 plays crucial roles in the regulation of HMGCR by FSH. FSH upregulates the SREBP-2 maturation (SREBP-2 -(N)), and the effect of FSH on HMGCR disappeared when SREBP-2 was inhibited by shRNA. The forkhead box protein O1(FoxO1) recognizes the insulin response element sites of the SREBP-2 promoter, and after FSH treatment, the binding ability of FoxO1 to the promoter decreases. Consequently, SREBP-2 transcription is reduced, driving nascent transcription of HMGCR and de novo cholesterol biosynthesis.132 PRL PRL is a polypeptide produced primarily by the anterior pituitary gland and has a lactogenic effect in the reproductive system when it binds to the prolactin receptor (PRLR). Recent studies have discovered that prolactin not only acts on the mammary gland but is also expressed in other metabolic tissues.133,134 Therefore, the role of PRL in the development of MASLD has become a significant topic of recent research. A clinical study has shown that the relationship between serum PRL and MAFLD risk was more pronounced in women than in men.135 Research indicates that PRL has an anti-lipogenic effect by downregulating lipoprotein lipase and fatty acid synthase, offering protective effects on the liver.136 Zhang P et al. suggested that PRL/PRLR may slow the liver lipid accumulation process by inhibiting CD36 in hepatocytes. This process is accompanied by the activation of signal transducer and activator of transcription 5.22 CD36 is an free fatty acid (FFA) transporter that promotes FFA uptake; increased CD36 expression in the liver leads to lipid deposition through enhanced liver fatty acid uptake and TG storage.137,138 Moreover, PRL has been observed to reduce the expression of SCD1, the rate-limiting enzyme in monounsaturated fatty acid biosynthesis, thereby protecting against hepatic steatosis.139 Currently, the mechanisms through which PRL improves hepatic lipid metabolism are still limited, and more studies are needed to provide a new basis for PRL-targeted treatment of MASLD. The molecular mechanisms by which sex hormone influences the pathogenesis of MASLD are described below and summarized in Table 1 and Figure 2. Table 1. | Sex hormone | Receptor | Mechanism | Reference | | |---|---|---|---|---| | Estrogen | ERα、ERβ、GPER | Activating AMPK | - • Inhibit ATP consumption and promote ATP production, leading to reduced liver lipogenesis and increased fatty acid oxidation | 35, 41, 48, 49, 50 | - • Reduce adipogenesis and promote fatty acid oxidation by maintaining the phosphorylation of ACC | |||| - • Decrease expression of relevant lipid synthesis genes by activating ERK and inhibiting SREBP1 production | |||| | Inhibiting JNK | - • Reduce the expression of liver Sab protein transformed from phospho-JNK | 53, 54, 55, 56 | || - • Mitigate the damage to the respiratory and electron transport chains in mitochondria | |||| - • Reduce ROS release | |||| | Activating PPARα | - • Reduce liver ROS pool by detoxifying hydrogen peroxide | 58, 59, 60, 61, 71 | || - • Upregulating catalase expression and activity to improve oxidative stress | |||| - • PPAR/retinoid X receptor complex can interact with ER, inhibiting transactivation by ER by competing for the estrogen response element | |||| | Activating PGC1 | - • Interact with various transcription factors to regulate the expression of fatty acid oxidation and anti-oxidative stress genes | 73, 74, 75, 76, 78 | || - • Promote fatty acid oxidation and reducing the production of ROS in mitochondrial | |||| - • Reduce the production of ROS in mitochondrial | |||| - • PGC1β can compensate for oxidative stress when PGC1α is completely absent | |||| | Androgen | AR | Activating NF-κB | - • Elevate the levels of TNF-α, IL-1β, IL-6, AST, ALT and hs-CRP, suggesting the establishment of a chronic low-grade inflammatory state characteristic of metabolic dysfunction-associated MASLD | 88, 89, 90 | - • Regulate the progression of hepatic fibrosis in three distinct ways: | |||| - 1) By modulating inflammatory signaling pathways associated with macrophages and other inflammatory cells in the liver | |||| - 2) By regulating the initial injury to liver cells that triggers fibrosis | |||| - 3) By influencing the fibrotic response of HSCs | |||| | Activating BCAA | - • Decrease activity of liver fatty acid elongase 2 | 92, 94 | || - • Activate mTORC1 signaling, leading to the serine phosphorylation of IRS-1 and IRS-2 and exacerbating IR | |||| | Activating SREBP1 | - • Increase the levels of SCAP and SREBP1 mRNA and protein by enhancing AR and SCAP intron 8 binding | 96, 98 | || - • Increase the proteolytic SREBPs transported to the nucleus | |||| - • Increase DNL, leading to increased hepatic lipid accumulation | |||| | SHBG | – | Being activated by HNF-4α | - • Stimulate SHBG promoter activity to increase SHBG expression | 107, 108, 109, 110, 111, 112 | - • DNL leads to the downregulation of HNF-4α expression, resulting in decreased SHBG expression | |||| - • TNF-α decreases mRNA and protein expression of HNF-4α and inhibits the production of SHBG through NF-κB signaling pathway | |||| - • IL-1β can downregulate HNF-4α, leading to the reduction of plasma SHBG and liver SHBG mRNA levels | |||| | Inhibiting ACC | - • Overexpression of SHBG blocks the increased levels of ACC genes | 20 | || | FSH | FSHR | Reducing the beiging of adipose tissue | - • Inhibit UCP-1 expression, which could decrease the mitochondrial biosynthesis and lead to fat accumulation | 123, 127 | | Activating ACSL | - • Activate fatty acids to form acyl-CoA involved in long-chain fatty acid metabolism | 128 | || | Inhibiting SREBP-2/FoxO1 | - • Reduce the binding ability of FoxO1 to the IRE sites of SREBP-2 promoter | 132 | || - • Reduce SREBP-2 transcription to drive HMGCR nascent transcription and de novo cholesterol biosynthesis | |||| | PRL | PRLR | Inhibiting CD36 | - • Enhance liver FA uptake and triglyceride storage | 22, 138, 137 | | Inhibiting SCD1 | - • Reduce the biosynthesis of monounsaturated fatty acids | 139 | ER, estrogen receptor; GPER, transmembrane G protein-coupled estrogen receptor; AMPK, adenosine monophosphate-activated protein kinase; ATP, adenosine 5′-triphosphate; ACC, acetyl-CoA carboxylase; ERK, extracellular signal-regulated kinase; SREBP, sterol regulatory element-binding transcription factor; JNK, c-Jun N-terminal kinase; Sab, SH3 domain-binding protein 5; ROS, reactive oxygen species; PPARα, peroxisome proliferator-activated receptor α; PGC1, peroxisome proliferator-activated receptor γ coactivator 1; AR, androgen receptor; NF-κB, nuclear factor kappa B; IL, interleukin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; hs-CRP, high-sensitivity C-reactive protein; BCAA, branched-chain amino acids; mTORC1, rapamycin complex 1; IRS, insulin receptor substrate; IR, insulin resistance; SCAP, SREBP cleavage-activating protein; DNL, de novo lipogenesis; SHBG, sex hormone-binding globulin; HNF-4α, hepatocyte nuclear factor-4α; FSH, follicle-stimulating hormone; FSHR, follicle-stimulating hormone receptor; UCP-1, uncoupling protein-1; ACSL, acyl-CoA synthetase; acyl-CoA, acyl-coenzyme A; FoxO1, forkhead box protein O1; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; PRL, prolactin; PRLR, prolactin receptor; FA, fatty acid; SCD1, stearoyl-CoA desaturase 1; MASLD, metabolic dysfunction-associated steatotic liver disease. RELATIONSHIP BETWEEN SEX HORMONES AND MASLD IN PCOS AND MENOPAUSE PCOS and MASLD PCOS is a common gynecological disorder characterized by hyperandrogenemia, ovulatory dysfunction, and polycystic ovary morphology.140 Women diagnosed with PCOS have shown a higher prevalence of MASLD and MASH, as indicated by liver biopsies and abdominal ultrasounds.141,142 A retrospective study utilizing a large United Kingdom primary care database, which included 63,120 women with PCOS and 121,064 matched control women, revealed that the prevalence of MASLD is notably higher among PCOS patients compared with the general population. Excessive androgen levels are key underlying factors contributing to the progression of MASLD in these patients,143 along with IR, central obesity, and dyslipidemia.140 Cui et al. conducted a study using DHT-exposed female rats to simulate PCOS conditions.88 Their findings indicated that long-term androgen excess led to increased lipid deposition in hepatocytes, elevated hepatic cholesterol levels, and a tendency for higher FFA levels. Additionally, oral glucose tolerance tests and insulin release tests demonstrated significant IR in the DHT group. Hyperandrogenemia has been linked to increased production of ROS and apoptosis,144 further complicating the metabolic landscape in these patients. The disruption of electron transport, activation of NF-κB signaling, and elevation of inflammatory factors, including L-1β, IL-6, and TNF-α were also observed,88 suggesting a greater propensity for developing MASH among individuals with both PCOS and MASLD.145 Furthermore, the dysfunction of hepatocyte mitochondria, disruption of electron transfer and aerobic respiration, enhanced oxidative stress, and reduced antioxidant effects were also observed. This result appears to correlate with PGC-1α, where specific reduction in PGC-1α in the liver reduces fatty acid oxidation and exacerbates hepatic IR.146 The levels of phosphorylated AMPKα (p-AMPKα) and the p-AMPKα/AMPKα ratio were significantly lower in DHT-treated rats, highlighting the role of AMPK in regulating metabolic adaptation by influencing mitochondrial biogenesis and biosynthetic gene expression.147 SHBG is regarded as a sensitive biomarker for MASLD, capable of reducing lipogenesis by downregulating key lipogenic enzymes in the liver.20 Given that hyperandrogenemia is a defining feature of PCOS, SHBG serves as a valid adjunct marker for assessing androgen levels.148 It can be inferred that the assessment of the PCOS progression severity ought to consider the serum SHBG levels. Lower SHBG levels have been related to a higher risk of MASLD in women with PCOS.149,150 SHBG levels are regulated by inflammatory factors such as TNF-α, IL-1β, and adiponectin, which are implicated in MASLD's pathogenesis. The downregulation of HNF-4α also contributes to reduced SHBG levels.110, 111, 112,116 Moreover, SHBG overexpression can further downregulate the mRNA and protein levels of ACC, a pivotal enzyme in lipogenesis, thus impeding the progression of MASLD.20 Menopause and MASLD Menopause is a significant transition in a woman's life, associated with various metabolic and physiological changes. A number of studies indicate that postmenopausal women are more susceptible to MASLD and experience a higher incidence of severe liver fibrosis compared with their premenopausal women. In view of this increased risk, it is crucial to explore the mechanisms by which menopause contributes to MASLD and to develop preventive and therapeutic methods for the pathophysiological changes. Data from the National Health and Nutrition Examination Survey (NHANES III) show that postmenopausal women are twice as likely to develop MASLD as premenopausal women. Interestingly, those receiving HRT exhibit a decreased risk of developing MASLD.151 Additionally, women undergoing abnormal menopause, such as surgically induced menopause, face nearly double the risk of severe hepatic fibrosis compared with those with natural menopause.152 This difference is strongly linked to changes in sex hormones, particularly estrogen deficiency. Kamada et al. simulated the progression of MASLD in postmenopausal women using ovariectomized mice fed a high-fat and high-cholesterol diet. After six weeks, the ovariectomized mice exhibited elevated serum cholesterol levels, exacerbated liver damage, and increased macrophage infiltration compared with control mice. However, estrogen treatment significantly improved hepatic inflammation and fibrosis, highlighting estrogen's essential role in preventing liver damage.15 Oxidative stress is another contributing factor to the pathogenesis of MASLD in postmenopausal women. PGC1α is crucial for fatty acid oxidation and enhancing hepatic insulin sensitivity.146The high expression of PGC1s in the liver of female mice reduces the production of ROS to improve mitochondrial function and thus alleviate MASLD, and the participation of estrogen in this process is essential.77 Studies have shown that increased expression of indicators of inflammation and fibrosis, and reduced levels of antioxidant enzymes were observed in the liver tissues of mice, with decreased PGC1α on a high-fat diet,77 suggesting that loss of estrogen signaling in postmenopausal women may contribute to the development of mitochondrial dysfunction and oxidative stress through reduced PGC1α expression. Therefore, strategies aimed at reducing oxidative stress and enhancing PGC1α expression in postmenopausal women may be effective in preventing and treating MASLD. Menopause is also related to increased levels of proinflammatory cytokines, such as IL-1, IL-6, and TNF-α.153 Tomoko Ohashi et al. found significant inflammation and increased macrophage presence in ovariectomized mice, potentially due to elevated monocyte chemoattractant protein-1.154 E2 can trigger a decrease in the spontaneous secretion of proinflammatory cytokines in peripheral blood cultures.155 Estrogen may exert anti-inflammatory effects by inhibiting proinflammatory cytokine secretion, thereby reducing the inflammatory state of the liver. In addition, estrogen also plays an anti-inflammatory role in human studies. Studies indicate that postmenopausal women showed decreased levels of CD4+ cells and B lymphocytes, reducing cytotoxic activity of natural killer cells, resulting in increased levels of proinflammatory cytokines and an inflammatory state in tissues.156,157 There is a complex relationship between testosterone levels and MASLD in women, with conflicting results regarding menopausal status. One study using NHANES Ⅲ data suggested that low total testosterone levels may be related to MASLD in postmenopausal women but not in premenopausal women.158 In contrast, another study found the relationship between testosterone levels and MASLD in 613 women stratified by menopausal status. After adjusting for covariates, the odds ratio of MASLD in premenopausal women increased with the rise in testosterone levels. However, similar association was not found in postmenopausal women.159 The mechanisms associated with menopause are also unclear. It was mentioned that hyperandrogenemia was associated with IR, increased visceral adipose tissue, and decreased skeletal muscle mass.19,83 However, this conflicting results indicated that the effect of androgen on MASLD in women may vary depending on menopausal status. APPLICATION PROSPECT OF SEX HORMONE IN THE TREATMENT OF FEMALE MASLD In recent years, the application of sex hormones in treating MASLD in women has gained considerable interest. Women with MASLD are mainly characterized by decreased or even lack of estrogen levels, making estrogen supplementation a primary strategy for hormone therapy. This supplementation can be categorized into two types: direct exogenous estrogen administration and estrogen replacement therapy. However, the roles of other sex hormones, such as androgens and SHBG, in MASLD treatment require further investigation. D'Eon et al. demonstrated that implanting estrogen pellets in ovariectomized mice led to inhibited liver lipogenesis.160 Their study found that the mRNA expression of enzymes involved in peroxisomal and mitochondrial β-oxidation was significantly reduced in androgen receptor knockout mice. Supplementation with 17β-estradiol ameliorated these deficiencies, bringing liver lipid content back to levels comparable to wild-type mice.14 These findings support the potential for sex hormones to play a therapeutic role in managing female MASLD. Thus, the following sections will elaborate on the potential therapeutic approaches involving sex hormones in the context of female MASLD. HRT HRT has been widely used in clinical practice, firmly establishing itself as the gold standard in alleviating menopausal symptoms, particularly for postmenopausal vasomotor and vaginal issues. However, HRT carries significant risks for stroke, cardiovascular disease, breast cancer, and venous thromboembolism.161 Consequently, it is not recommended for long-term use.162 Research by McKenzie J. et al. investigated the effects of HRT on liver enzyme levels in postmenopausal women with T2DM. Their findings indicated that patients who received HRT for six months or more had significantly reduced serum levels of ALT, AST, gamma-glutamyl transferase (GGT), and alkaline phosphatase compared with those who were on HRT for less than six months.163 Another study noted a lower prevalence of MASLD among postmenopausal women receiving HRT, while those not on HRT had a higher incidence of metabolic syndrome.164 Conversely, some studies suggest that HRT may increase the risk of severe hepatic lobular inflammation in postmenopausal women, with researchers attributing this increased risk to progesterone rather than estrogen.165 This conflicting evidence necessitates further research to confirm the role of HRT in the treatment of MASLD. Additionally, studies have shown that elevated SHBG levels can improve MASLD, with an average increase of 141.7 nmol/l after 3–6 months of combined oral contraceptive use.166 Furthermore, estrogen 4 (E4) has recently gained attention as a potential treatment for menopausal symptoms and is a major component of a novel combined oral contraceptive (E4/drospirenone [DRSP]).167 However, due to its limited effects on liver enzyme levels and coagulation parameters, more research is needed to ascertain whether E4 is a viable option for treating MASLD.168 Selective Estrogen Receptor Modulators and Tissue-Selective Estrogen Complexes Selective estrogen receptor modulators (SERMs) have been widely used in recent years for their ability to bind to ER and mimic the function of estrogen. The commonly used SERMs include tamoxifen, raloxifene, and bazedoxifene(BZA). Among these, tamoxifen has been associated with inducing MASLD, while raloxifene, which is approved for preventing breast cancer and osteoporosis, has shown potential in upregulating ER expression and alleviating liver inflammation.14,25,169 However, most SERMs tend to exacerbate menopausal symptoms such as vasomotor symptoms.170 BZA represents a notable SERM with beneficial effects. Studies indicate that when combined with conjugated estrogens (CEs) to form tissue-selective estrogen complexes (TSECs), BZA can improve metabolic problems associated with postmenopausal symptoms. This combination not only prevents osteoporosis in postmenopausal women but also inhibits breast tumor growth.171,172 Moreover, the combination can significantly reduce the frequency and severity of vasomotor symptoms associated with SERMs alone.173 Recent findings suggest that BZA/CE treatment decreases liver lipid deposition by promoting hepatic lipid oxidation174 and enhancing insulin action, thereby improving IR.175 Furthermore, it appears to downregulate human complement factor D homolog (Cfd), a factor that promotes lipogenesis.176,177 Phytoestrogens Phytoestrogens have emerged as a hot topic in MASLD treatment. These natural estrogens extracted from plants can bind to ER and mimic estrogen's effects. The isoflavone, in particular, has been recognized as one of the most potent estrogenic compound, including daidzein, glycitein, genistein, biochanin A, and formononetin.178 Daidzein and genistein are primarily found in soy and soy products, making them significant dietary sources for humans.179 Phytoestrogens function similar to SERMs because they can act as both estrogen agonists and antagonists.180 They may also influence the synthesis of SHBG and indirectly affect endogenous estrogen levels by binding to and inactivating specific enzymes. A study involving 6786 Chinese adults investigated the correlation between dietary isoflavone consumption and metabolic disorders. The findings revealed a negative association between MASLD and the intake of genistein, daidzein, and overall isoflavone consumption.181 Genistein Genistein, a prominent phytoestrogen found in soybeans, is extensively studied for its effects on various signaling pathways related to cancer, obesity, and metabolic syndrome.182 Recent research has highlighted its potential therapeutic benefits for MASLD. In animal studies, genistein has been shown to reduce body weight and abdominal circumference in mice on a high-fat diet, with effects that are dose-dependent.183 Additionally, genistein appears to mitigate hepatic fat accumulation by activating the AMPK pathway, upregulating PPARγ expression, and enhancing mitochondrial enzymatic activity.183, 184, 185 Given the risk of MASLD progressing to HCC, genistein's ability to significantly inhibit the growth of hepatocellular adenomas in HCC-LM3 cells suggests promising avenues for its application in preventing or treating MASLD.186 Daidzein A cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) investigated the relationship between daidzein intake and MASLD in 1476 participants. The findings revealed that higher daidzein intake was associated with a decrease in the prevalence of MASLD, fatty liver index, and hepatic steatosis index (HSI,187 suggesting that adequate daidzein consumption may help improve hepatic steatosis. Besides, daidzein can also alter lipid metabolism through PPARγ.188 The inhibition of inflammation and oxidative stress which can damage hepatocytes is also one of the main mechanisms by which daidzein improves MASLD.189 Therefore, it is recommended that females increase their consumption of soy and soy products to mitigate the risk of MASLD and slow its progression. However, an etiological analysis linked excessive soy consumption to issues such as uterine myomas, endometriosis, endometrial fibrosis, and secondary infertility,190 highlighting the need for strict control in phytoestrogen intake when considering treatment options for MASLD. The application of sex hormones in treating female MASLD is summarized in Table 2. Table 2. | Sex hormone -related treatment | Advantages | Side-effects | References | | |---|---|---|---|---| | HRT | Reducing serum concentrations of liver function enzymes such as ALT, AST, GGT, ALP | HRT carries significant risks for stroke, cardiovascular disease, breast cancer, and venous disease | 161, 162, 163, 164, 165 | | | SERMs | Raloxifene upregulate ER expression and improve liver inflammation | Tamoxifen induce MASLD; SERMs exacerbate vasomotor symptoms in menopause women | 14,25,169,170 | | | TSECs | Promoting hepatic lipid oxidation; Downregulating Cfd; Preventing osteoporosis and vasomotor symptoms in menopause; Suppressing the growth of breast tumor | – | 171, 172, 173, 174, 175, 176, 177 | | | Phytoestrogens | Genistein | Reducing hepatic fat accumulation; Suppressing the growth of hepatocellular adenomas in HCC-LM3 cells | Excessive consumption of phytoestrogens was associated with uterine myomas, endometriosis, endometrial fibrosis, and secondary infertility | 182, 183, 184, 185, 186 | | Daidzein | Altering lipid metabolism; Inhibiting inflammation and oxidative stress in hepatocyte damage; Deceasing the prevalence of MASLD, FLI, and HSI | 187, 188, 189, 190 | HRT, hormone replacement therapy; SERMs, selective estrogen receptor modulators; TSECs, tissue-selective estrogen complexes; MASLD, metabolic dysfunction-associated steatotic liver disease; ER, estrogen receptor; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; ALP, alkaline phosphatase; Cfd, human complement factor D homolog; FLI, fatty liver index; HSI, hepatic steatosis index. With rapid changes in lifestyles, the harmful impact of MASLD on public health has become increasingly apparent and poses one of the major challenges globally. Previous studies have shown a sex difference in MASLD prevalence.12 In females, sex hormone levels are strongly associated with the development of MASLD. This article reviewed the role and application of female sex hormones in MASLD and discussed its pathophysiological mechanisms. In summary, estrogen has a protective effect on the occurrence and development of female MASLD. It can improve the imbalance of liver lipid metabolism and reduce the abnormal formation of liver collagen by regulating AMPK, JNK, PPARα, PGC1 and other molecular pathways, thereby delaying the progression of MASLD and MASH.39,46 In contrast, androgens are among the primary contributors to the accelerated development of MASLD in females. However, there is limited research on the signaling pathways through which androgens promote female liver steatosis. This paper discussed molecular changes such as NF-κB, BCAA, and SREBP1, which may assist in further research on anti-androgen agents for MASLD treatment. SHBG is the primary glycoprotein involved in sex hormone transport, and its levels are negatively correlated with the occurrence of disease in both men and women. SHBG is not only an important indicator of MASLD development, regulated by HNF-4α, but also impacts MASLD pathogenesis by downregulating key enzymes in hepatic lipogenesis. Furthermore, there are few studies related to other sex hormones, such as FSH and PRL, and their roles in MASLD remain controversial and require further investigation. Hyperandrogenemia is the most prominent feature in women with both PCOS and MASLD, and anti-androgen therapy may be the best option for these patients. Additionally, SHBG has been shown to significantly increase the risk of MASLD in PCOS patients, suggesting that future drugs targeting SHBG may offer therapeutic benefits. Menopause is accompanied by dramatic changes in sex hormone levels; decreased estrogen levels promote the development of MASLD along with changes in inflammatory cytokines and mitochondrial dysfunction, while the association between androgens and menopause remains controversial. Women with MASLD may benefit from increased research into the application of sex hormones for disease treatment, including HRT, SERMs, TSECs, and phytoestrogens. It is essential to develop new drugs targeting sex hormones while minimizing their side-effects in the future. Credit authorship contribution statement Huiyan Duan contributed to literature searching, data curation, validation, writing–original draft. Minmin Gong contributed to figure and table correction. Gang Yuan and Zhi Wang contributed to writing–review and editing, project administration, and supervision. Funding This study was supported by the National Natural Science Foundation of China (No. 82270855). Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gang Yuan reports financial support was provided by the National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

No application. Contributor Information Gang Yuan, Email: [email protected]. Zhi Wang, Email: [email protected].

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