Pathophysiology of depression and anxiety in metabolic dysfunction-associated steatotic liver disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease with a continually rising global prevalence and significant mortality rates. Emerging evidence suggests a strong association between MASLD and mental health disorders such as depression and anxiety. In addition to the shared risk factors such as obesity, type 2 diabetes and insulin resistance which contribute to this relationship through mechanisms involving systemic inflammation and oxidative stress; other pathophysiological mechanisms such as dysregulation of hypothalamic-pituitary-adrenal axis, neurotransmitter imbalances and gut dysbiosis have also been proposed to play a significant role. The current paper aims to review the pathophysiological mechanisms underlying the association between MASLD and mood disorders such as depression and anxiety. We note a bidirectional relationship between these two disorders, and the dual burden of both these disease processes can be alleviated by early detection and encouraging a more proactive and holistic approach through diet and lifestyle changes. This review summarizes the existing literature on association between MASLD and depression.

Core Tip: Metabolic dysfunction-associated steatotic liver disease is associated with mood disorders such as depression and anxiety through shared pathophysiological pathways. This review links systemic inflammation, hypothalamic-pituitary-adrenal axis dysregulation, gut dysbiosis, and neurotransmitter imbalances as mediators of this bidirectional relationship. We highlight how overlapping risk factors such as insulin resistance, obesity, sarcopenia, poor sleep, and physical inactivity exacerbate both the disease processes. Recognizing the mental health burden allows for improved patient outcomes and supports a holistic, lifestyle-focused treatment model that addresses both physical and mental health.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is characterized by the accumulation of fat in the liver and is associated with metabolic abnormalities, including obesity, insulin resistance (IR), and type 2 diabetes[1,2]. In 2023, a global Delphi consensus recommended transitioning from the term NAFLD to MASLD to better reflect the metabolic dysfunction underlying the condition and move away from stigmatizing terminology such as "nonalcoholic" and "fatty". The revised nomenclature recognizes steatosis in the presence of at least 1 of 5 cardiometabolic risk factors as a positive diagnostic criterion. It introduces related categories such as metabolic dysfunction-associated steatohepatitis (MASH) and MetALD for overlapping alcohol-related cases[3]. MASLD prevalence has increased from about 25% to nearly 34% over 18 years, highlighting its growing public health impact along with rising rates of obesity and metabolic syndrome[4-6]. In addition to its clinical burden, MASLD causes a significant financial burden. Medical costs in the United States exceed $62 billion, averaging $1584 per patient, and affecting over 39 million Americans. Once considered a condition confined to the liver, MASLD is now recognized as a complex, systemic disorder driven by metabolic dysfunction and chronic inflammation. It is associated with a variety of extrahepatic manifestations, including cardiovascular disease, type 2 diabetes, chronic kidney disease, hypothyroidism, polycystic ovarian syndrome, and psoriasis[7-10].

Studies have also reported MASLD to be linked to mental health disorders, particularly depression and anxiety[11]. Studies show that individuals with MASLD experience a significantly higher prevalence of anxiety and depression compared to the general population[12,13]. A recent meta-analysis reported that among adults with MASLD, the prevalence of depression was approximately 26%, anxiety was around 37%, and stress as high as 51%[14]. This highlights the significant psychological burden associated with the condition. While the relationship between MASLD and mental health disorders is becoming increasingly apparent, the biological mechanisms driving this relationship continue to be poorly understood. However, several hypotheses have been postulated, including gut microbiota dysbiosis as a potential contributor[15,16]. While awareness of the mental health challenges linked to MASLD is increasing, our understanding of the biological mechanisms behind these associations is still limited. This gap underscores the need for integrative research that explores how metabolic, inflammatory, and neurological pathways might connect liver dysfunction with mental health conditions like anxiety and depression. At a molecular level, mood disorders like depression and anxiety arise from complex interactions within the body’s immune, endocrine, and nervous systems. Chronic low-grade inflammation and overactivity of the hypothalamic-pituitary-adrenal (HPA) axis are key mechanisms linked to depression and anxiety[17-20]. Increasing levels of pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), impair neuroplasticity and neurogenesis, contributing to mood disturbances[21,22]. Interestingly, these same inflammatory pathways have been implicated in the pathogenesis of MASLD[23-25].

Despite growing awareness, current treatments for MASLD and mood disorders often focus on each condition in isolation, missing the shared pathophysiological basis[26].

Even emerging therapies like HPA modulators and microbiota-based interventions show mixed results, pointing to the need for more integrated and personalized approaches[27,28]. In this review, we focus on current findings to provide an updated perspective on the mechanisms that may underlie these associations. Clarifying these connections could pave the way for earlier screening and more holistic treatment approaches that will ultimately help in improving both the physical and psychological outcomes for individuals living with MASLD.

A literature search was conducted between March and May 2025 using the databases PubMed, Scopus, and Google Scholar. Search terms included a combination of MeSH terms and keywords which were “MASLD”, “NAFLD”, “depression”, “anxiety”, “neuroinflammation”, “gut-brain axis”, “obesity”, “HPA axis”, “sarcopenia”, “cytokines”, and “insulin resistance”. Boolean operators (AND/OR) were applied as appropriate. Only articles published in English were included. We included both original research articles and review articles to contextualize and interpret findings. No formal exclusion criteria were applied. Reference lists of eligible studies were screened manually to identify additional literature that could provide mechanistic insight where direct associations were not available.

EPIDEMIOLOGY

A meta-analysis study done by Younossi et al[29] which included 92 population-based studies covering over 9.36 million individuals globally, showed a striking rise in the global prevalence of MASLD. Between 1990 and 2019, global MASLD prevalence increased by 50.4%, rising from 25.26% in 1990–2006 to 38.2% in 2016–2019. The association between MASLD and mood disorders has become evident. It has been previously reported by multiple studies that patients with MASLD have a higher prevalence of depression (27.2%) than that of the general population[30-32]. A cross-sectional Brazilian study found an inverse association of MASLD with anxiety [odds ratio (OR) = 0.75, 95%CI: 0.63-0.90] and a positive association with depression (OR = 1.17, 95%CI: 1.00-1.38)[33]. A 2020 study by Labenz et al[34] conducted over a 10 years period showed that 21.2% of MASLD patients developed depression (vs 18.2% of controls), while 7.9% developed anxiety (vs 6.5%). According to Youssef et al[13], the severity of depressive symptoms increased with the severity of hepatocellular ballooning. Brodosi et al[35], interestingly, stated that disease severity did not consistently correlate with psychiatric burden, possibly due to a general lack of awareness of MASLD’s progressive nature among patients. MASLD was not independently associated with moderate/severe depression (OR = 0.34; 95%CI: 0.12–1.01) or severe trait anxiety (OR = 0.79; 95%CI: 0.27–2.34).

However, according to Tomeno et al[31], the severity of steatosis was greater in MASLD patients comorbid with depression than those without. These discrepancies may stem from a number of potential reasons. The study by Brodosi et al[35] was cross-sectional and relied on self-reported psychiatric symptoms through questionnaires. Labenz et al[34], on the other hand, conducted a longitudinal analysis using a large primary care database over 10 years, capturing incident cases of depression and anxiety. Differences in methods to diagnose MASLD such as biopsy in Tomeno et al[31] vs imaging or International Classification of Diseases coding in others can also be a reason for variability in results. Furthermore, population characteristics such as referral setting and presence of metabolic comorbidities likely influenced the strength and direction of observed associations.

The association between MASLD and mood disorders may be gender specific. A retrospective cross-sectional study conducted in a Korean population suggested that women with MASLD were more prone to suffer from anxiety and depression as the severity of steatosis increased[11]. Similarly, Jung et al[36] reported that women with MASLD had a higher prevalence of depression compared to men. A 2025 study by He et al[37] used central fat distribution as a mediator between MASLD and depression suggesting that it explains about 16.6% of the link between MASLD and depression overall. In females, this mediating effect was found to be statistically significant accounting for 17.83% of the link. Women with diabetes and women, in general, experience a higher prevalence of depression than men[38,39]. In the Brazilian study by Goulart et al[33], only men presented an association of anxiety with MASLD (OR = 0.73; 95%CI: 0.60-0.89) when sex-stratified analyses were done. The prevalence of depression is twice as high in people with type 2 diabetes (19.1%, range 6.5%-33% vs 10.7%, range 3.8%-19.4%) compared to those without[38].

This relationship has been suggested to be bidirectional. A two-step Mendelian randomization analysis concluded that people who are genetically predisposed to depression are at risk of developing MASLD (OR = 1.557; 95%CI: 1.097–2.211; P = 0.016)[40]. However, this study disproved causality in the other direction. Data from the United Kingdom Biobank, as referenced in recent longitudinal research, displayed that individuals with depression have an increased risk of developing MASLD (hazard ratio = 1.21; 95%CI: 1.09–1.34)[41]. Increased incidence of depression and anxiety was found in a cohort of adolescents with MASLD. In this cohort, the incidence of new depression and anxiety cases in MASLD was 27 and 18 per 1000 person-years, respectively. Concurrently, levels of alanine aminotransferase worsened for adolescents with MASLD who developed depression compared to those who did not develop depression[42]. A 2022 Longitudinal study done in a Southern California population exhibited that individuals with MASLD and higher levels of physical activity were at a decreased odds of having depressive symptoms [16.1% reduction (95%CI: -25.6 to -5.4%), P = 0.004], which was not observed in those without MASLD taking into account various comorbidities (i.e., age, sex, diabetes, hypertension, obesity)[43]. MASLD patients develop sarcopenia, which makes them more prone to depressive symptoms, potentially due to diminished physical capacity and fatigue[44-46]. Additional at-risk groups include women with polycystic ovary syndrome, who often experience both MASLD and high risk of depression[47-49]. The current epidemiology is summarized in Table 1.

Table 1.

Key studies highlighting the increased risk of depression and anxiety in patients with metabolic-associated steatotic liver disease

Ref.	Year	Type	Population	Key findings
Weinstein et al[30]	2011	Cross-sectional study. MASLD was diagnosed through pathology and/or radiologic testing	878 patients with chronic liver disease (MASLD, HBV, HCV) seen at a tertiary liver center	MASLD patients had a significantly higher prevalence of depression (27.2%). Independent predictors of depression for MASLD patients included hypertension, current smoking, history of lung disease, female sex, and nonAfricanAmerican ethnicity
Goulart et al[33]	2023	Cross-sectional study. MASLD was diagnosed by ultrasound imaging	7241 working-age adults from a primary care center in Brazil. Comorbidities included metabolic syndrome components such as obesity, diabetes, dyslipidemia and hypertension	MASLD was positively associated with depression (OR = 1.17, 95%CI: 1.00-1.38). MASLD was inversely associated with anxiety (OR = 0.75, 95%CI: 0.63-0.90) and when stratified by sex, only men presented this association (OR = 0.73; 95%CI: 0.60-0.89)
Christian Labenz et al[34]	2020	Retrospective cohort study. MASLD diagnosed primarily by ICD codes in primary care records	19871 German adults with an initial diagnosis of MASLD/MASH without liver cirrhosis matched with 19871 controls from German primary care records between years 2010–2015. Comorbidities such as type 2 diabetes, obesity, and cardiovascular disease were accounted for using the Charlson Comorbidity Index in the analysis	MASLD patients had a higher incidence of both depression (21.2% vs 18.2%) and anxiety (7.9% vs 6.5%) compared to controls. After adjusting for confounders, MASLD remained an independent risk factor, with hazard ratios of 1.21 for depression and 1.23 for anxiety
Youssef et al[13]	2013	Cross-sectional study. MASLD diagnosed by liver biopsy	567 biopsy-proven MASLD patients enrolled in the Duke MASLD Clinical Database. Comorbidities including diabetes and obesity were reported and considered	14% of patients were noted to have clinical depression while 23% had clinical anxiety. The severity of depressive symptoms increased with the severity of hepatocellular ballooning with adjusted cumulative odds ratio of clinical depression 3.6 (95%CI: 1.4-8.8)
Brodosi et al[35]	2024	Cross-sectional study. MASLD diagnosed by ultrasound and/or clinical criteria	286 Italian adults out of which 223 met MASLD criteria. Comorbidities included obesity, diabetes, and hypertension reported among participants	MASLD was not independently associated with moderate/severe depression (OR = 0.34; 95%CI: 0.12–1.01) or severe trait anxiety (OR = 0.79; 95%CI: 0.27–2.34). This was attributed to awareness of MASLD progression by the patient
Tomeno et al[31]	2015	Prospective observational study. MASLD was diagnosed by biopsy	258 Japanese adults with biopsy confirmed MASLD, out of which 32 were diagnosed with depression	Patients comorbid with depression showed higher severity of steatosis and increased levels of serum aminotransferase, γ-glutamyl transpeptidase and ferritin
Choi et al[11]	2021	Retrospective cross-sectional study. MASLD was diagnosed by ultrasonography	25333 Korean adults among whom MASLD prevalence was 30.9%. Comorbidities including obesity, diabetes, and hypertension were reported	In women, MASLD was significantly associated with depression (adjusted OR = 1.43, 95%CI: 1.14–1.80; P = 0.002). Additionally, severe MASLD showed a significant correlation with both state anxiety (adjusted OR = 1.84, 95%CI: 1.01–3.37; P = 0.047) and trait anxiety (adjusted OR = 2.45, 95%CI: 1.08–4.85; P = 0.018)
He et al[37]	2025	Cross-sectional study. MASLD diagnosed by NHANES criteria including imaging and lab markers	3332 ethnically diverse MASLD patients drawn from NHANES dataset	Overall, central fat mediated 16.6% of the link between MASLD and depression. In women, the mediation by central fat was 17.8%, while no mediation was found in men
Roy et al[38]	2012	Systematic review	Adults with and without type 2 diabetes from multiple studies published between 2006 and 2011	Both, women with diabetes and also women without diabetes experience a higher prevalence of depression than men. The prevalence rate of depression is almost twice as high in people with type 2 diabetes (19.1%, range 65%-33% vs 10.7%, range 38-19.4%) than those without
Liang et al[40]	2024	Two-sample Mendelian randomization	807553 individuals, comprising 246363 cases and 561190 controls, derived from three GWAS conducted on individuals of European ancestry	Depression increased the risk of MASLD (OR: 1.557; 95%CI: 1.097-2.211; P = 0.016) but no inverse causal relationship was found
Zhou et al[41]	2024	Prospective cohort study followed by mendelian randomisation. MASLD diagnosed using United Kingdom Biobank clinical data	481181 United Kingdom Biobank participants after excluding participants with liver disease or alcohol/drug use disorders at baseline, without related exact date for liver disease or alcohol/drug use disorders, and new-onset severe MASLD within 5 years follow-up (median follow-up 13.5 years)	Participants with depression had a significantly higher risk of developing severe MASLD compared to those without depression (HR: 1.21, 95%CI: 1.09–1.34)
Noon et al[42]	2021	Prospective longitudinal cohort study. MASLD was diagnosed by liver biopsy	160 adolescents (ages 12–17) with MASLD followed for a mean of 3.8 years	At baseline, 8.1% had depression and 6.3% had anxiety. Over follow-up, an additional 95% developed depression (95%CI: 4.7%-14.3%) and 6.7% developed anxiety (95%CI: 2.6%-10.7%). Those who developed depression had significantly worse ALT changes in comparison to those without depression
Weinstein et al[43]	2022	Cross-sectional study	589 survey participants from a southern California community aged less than 70 years	After adjusting for various comorbidities, individuals with MASLD and higher levels of physical activity were at a decreased odds of having depressive symptoms [16.1% reduction (95%CI: -25.6 to -5.4%), P = 0.004], which was not observed in those without MASLD

MASLD: Metabolic dysfunction-associated steatotic liver disease; HBV: Hepatitis B virus; HCV: Hepatitis C virus; OR: Odds ratio.

Even though an overwhelming amount of evidence suggests that chronic conditions like hypertension, obesity, diabetes and coronary artery disease account for shared risk factors between MASLD and mood disorders such as depression, the exact shared pathogenesis remains poorly understood[37,50]. We’ve detailed the pathophysiological factors which link the two conditions in the upcoming sections.

Shared risk factors

IR and type 2 diabetes: IR is defined as diminished sensitivity of target tissues to respond to insulin. This leads to a compensatory response by pancreatic beta cells to increase plasma insulin concentration resulting in hyperinsulinemia[51]. This results in increased hepatic de novo lipogenesis via the dysregulation of key transcription factors, including sterol regulatory element-binding protein 1c and carbohydrate regulatory element-binding protein[52]. As a result, there is an overproduction of free fatty acids (FFAs) and lipid accumulation in hepatocytes which leads to hepatic steatosis or MASLD. IR disrupts the process of triglycerides (TGs) synthesis from FFAs and packaging into very low-density lipoprotein (VLDL) particles for storage or export, leading to lipid accumulation in liver cells and exacerbating hepatic steatosis[53]. Thus, MASLD occurs as the metabolic consequence of IR[54]. IR promotes excessive FFAs flux to the liver, inducing lipotoxicity and activating NF-κB mediated inflammatory cascades. Insulin normally exhibits anti-inflammatory effects. In the case of IR, it paradoxically leads to development of low-grade inflammation, especially in obese individuals[55]. This pro-inflammatory state in MASLD leads to abnormal microglial activation which mediates neuroinflammation[56]. Thus, IR promotes systemic low-grade inflammation, oxidative stress, and altered immune responses, all of which have been implicated in the pathophysiology of depression. Microglial activation has been implicated in the pathophysiology of both depression and anxiety[57-59].

Type 2 diabetes mellitus (T2DM) and MASLD usually co-occur, with more than 70% of T2DM patients presenting with MASLD[60,61]. T2DM independently increases the risk of major depressive disorder through mechanisms involving systemic inflammation, HPA axis dysfunction, and microvascular brain injury[62,63]. A study found that the prevalence rates of depression are up to two-fold higher in diabetic patients, in comparison to the general population[38]. Another study found that the generalised anxiety disorder is present in 14% and elevated symptoms of anxiety is present in 40% of patients with type 2 diabetes[64].

Obesity: In obese individuals, adipose tissue undergoes a phenotypic switch to a proinflammatory state from an anti-inflammatory M2 phenotype to a pro-inflammatory M1 phenotype[65]. Infiltration of M1 macrophages results in increased secretion of cytokines such as TNFα and IL6 which inhibit insulin signalling pathways[66]. Dysregulation of adipokines and elevated stem cell growth factor-beta (SCGF-β) levels also contribute to the pro-inflammatory state[67]. Obese individuals also exhibit significantly elevated levels of reactive oxygen species, which result in impaired insulin signaling, activation of pro-inflammatory pathways, endothelial dysfunction, and ultimately contribute to the development of IR and other components of metabolic syndrome[68]. All these pathophysiological mechanisms exacerbate IR, stimulate hepatic de novo lipogenesis, impair VLDL secretion, and promote TG accumulation in hepatocytes, laying the groundwork for MASLD[69].

Obesity and depression also share a complex, bidirectional relationship. The same pathophysiological processes that underlie obesity and MASLD are increasingly recognized as contributing to the development of depression as well. Leptin resistance and low levels of adiponectin correlate not only with obesity but also with decreased central activity and increased neuroinflammation[70,71]. Resistin and visfatin are elevated in obesity and are linked to pro-inflammatory pathways and HPA axis activation, both implicated in the pathogenesis of psychiatric disorders[72,73].

In women, visceral fat accumulation more strongly mediates the MASLD-depression relationship than in men[37]. Estrogen plays a protective role by modulating gut microbiota composition, suppressing systemic inflammation, and maintaining blood-brain barrier integrity, which limits the impact of circulating cytokines on mood regulation[74-76]. Estrogen also attenuates HPA axis reactivity, which may explain reduced stress sensitivity in premenopausal females[77]. In contrast, low testosterone in males is associated with increased adiposity and altered adipokine signaling, but lacks the neuroprotective effects seen with estrogen[78].

Beyond biological mechanisms, psychosocial factors may also be a possible link between mood disorders and obesity[79]. Chronic stress levels stimulate HPA axis activation resulting in appetite dysregulation and weight gain[80]. This promotes abdominal fat accumulation accompanied by emotional eating as a coping mechanism to reduce stress and anxiety. Stigma related to obesity, encompassing both perceived discrimination and internalized bias, has been shown to affect overall psychological well-being[81]. This stigma independently contributes to depression and anxiety symptoms in obese individuals. Overweight adolescents and young adults especially girls experiencing body image dissatisfaction are at significantly increased risk for depressive and anxiety symptoms as well[82,83].

Poor sleep, attitude towards health and exercise: Sleep is a key pillar of both physical and mental health. For people living with MASLD, poor sleep is unfortunately all too common and often overlooked[84]. Many patients experience trouble falling or staying asleep, and this chronic disruption can intensify feelings of anxiety and depression[85-87]. Obstructive sleep apnea (OSA) is known to have a strong independent association with metabolic diseases especially MASLD[88-90]. The intermittent oxygen deprivation and sleep fragmentation seen in OSA can fuel systemic inflammation and metabolic stress, further worsening both liver function and mood regulation[91-95].

Research shows that poor sleep contributes to inflammation and affects how our brain handles emotions, which helps to explain why sleep issues are strongly linked to both depression and worsening liver health in MASLD[96,97]. One cohort study conducted by Um et al[98] found that both sleep duration and sleep quality were closely related to liver disease progression, highlighting how sleep can make a major difference. Thus, prioritizing sleep health could make a meaningful difference in the holistic management of MASLD, potentially reducing the associated psychiatric burden and improving overall quality of life.

Alongside sleep, daily habits like physical activity can also play a big role in shaping mental health[99-101]. Many individuals with MASLD find it difficult to stay active, often due to fatigue, joint pain, or simply low motivation that can come with chronic illness[102-106]. But this physical inactivity can quietly contribute to emotional struggles. Regular physical activity has been shown to lower systemic inflammation, enhance neuroplasticity, and improve stress resilience, all of which protect against anxiety and depressive symptoms[107-110]. When patients disengage from physical activity and adopt more passive lifestyles, it can worsen both their physical condition and mental resilience. Botacin et al[111] highlight the link between poor lifestyle habits and elevated rates of anxiety and depression among MASLD patients. Lifestyle interventions remain central to managing both MASLD and comorbid mood disorders. Keating et al[106] describe a 24-hour integrated behavioral model that includes structured physical activity, sleep hygiene, and circadian-aligned eating. Moderate-to-vigorous aerobic and resistance training can reduce hepatic steatosis and improve mood through lower inflammation levels[112]. High-intensity interval training can be particularly effective in improving MASLD-related biomarkers[113]. However, it might not be an effective strategy in people with mood disorders due to low adherence[114]. The Mediterranean diet, rich in fruits, vegetables, whole grains, olive oil, and fish, has shown promise for MASLD. It prevents liver fat deposition and reduces IR. Its benefits may be amplified when combined with regular physical activity[115]. A randomized controlled trial found significant reductions in depression, anxiety, and stress following Mediterranean diet instructions[114]. A combined lifestyle intervention significantly reduces cortisol levels and improves liver steatosis in MASLD patients. In addition to physical benefits, these interventions also support emotional well-being. Participating in group exercise alongside psychosocial support boosts motivation and improves mood by stimulating endorphin release[116].

While lifestyle changes are first-line, pharmacologic treatments may be useful. SSRIs can relieve depression without harming liver function, but require careful monitoring[117]. Anti-inflammatory and hepatoprotective agents like vitamin E, pioglitazone, and GLP-1 receptor agonists may benefit both liver and mental health[118,119]. More research is needed to confirm their safety and effectiveness in this context.

Sarcopenia: Sarcopenia is increasingly prevalent in individuals with metabolic dysfunction, especially those with obesity, type 2 diabetes, and advancing age. Emerging evidence has shown its bidirectional association with MASLD. A recent meta-analysis showed that patients with MASLD have a significantly higher risk of developing sarcopenia[44,120]. Sarcopenia contributes to systemic inflammation, reduced insulin sensitivity, and decreased skeletal muscle glucose uptake resulting in accelerated MASLD progression[121,122].

Sarcopenia is also strongly associated with depressive and anxiety symptoms[123,124]. A 2022 meta-analysis encompassing over 25000 individuals reported a pooled depression prevalence of 28% among sarcopenic patients, with sarcopenia conferring a 71% increased risk of depression compared to non-sarcopenic controls[125]. Another study discussed the prevalence of sarcopenia and depressive symptoms among older adults, highlighting shared risk factors such as advanced age, malnutrition, obesity, diabetes, hypertension, cognitive impairment, and polypharmacy[126]. Population-based studies from Korea and Australia demonstrate that sarcopenia is independently associated with elevated anxiety scores, particularly in middle-aged and older adults[127]. These findings suggest that sarcopenia not only contributes to the systemic inflammation and sedentary behavior implicated in MASLD but also plays a central role in the emotional and psychological vulnerability observed in this population.

Proposed hypothesis

Systemic inflammation: Systemic inflammation was found to be one of the major common links between the pathogenesis of MASLD and Depression. A 2021 study by Xiao et al[23] suggested that increased levels of these proinflammatory cytokines may contribute to systemic inflammation leading to increased risk of depression and anxiety in MASLD patients. It has been well established in previous studies that inflammatory mediators play a major role in the development and progression of MASLD[24,128]. The mechanistic basis of systemic inflammation in MASLD is multifactorial, which encompasses IR, lipotoxicity, gut dysbiosis, visceral adiposity, and spillover of cytokines into circulation. Figure 1 illustrates the proposed pathway linking systemic inflammation in MASLD to neuropsychiatric sequelae[21,23,24,129]. Metabolic dysfunction (due to IR, obesity, or dyslipidemia) leads to accumulation of fat in the liver (steatosis) which can trigger inflammation eventually leading to liver cell injury. IR promotes excessive FFAs flux to the liver, inducing lipotoxicity and activating NF-κB mediated inflammatory cascades. In obese individuals, oxidative stress is presumed to be the major initiator of activation of inflammatory cascade derived from increased visceral adipose tissue. Thus, pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α are significantly implicated in the pathogenesis of MASLD[128,130]. This pro-inflammatory state in MASLD leads to abnormal microglial activation which mediates neuroinflammation. Microglial activation contributes to the pathophysiology of both depression and anxiety (Figure 1). In fact, recent studies regard depression as a microglial disease[129,131]. The excessive activation of microglia leads to release of more cytokines and initiates a neuroinflammatory response. This fact is reinforced by individual studies which have proved the prevalence of low grade systemic inflammation in patients of depression[21,22]. This neuroinflammatory response can disrupt neurotransmitter systems, particularly serotonin and glutamate pathways, which are vital for mood regulation. The activated microglia can impair neurogenesis, the process of generating new neurons, and synaptic plasticity, both essential for learning and emotional resilience. These changes can manifest as the cognitive and emotional symptoms observed in depression[131].

Figure 1.

Systemic inflammation and neuropsychiatric sequelae in metabolic dysfunction–associated steatotic liver disease. IL-6: Interleukin-6; IL-1β: Interleukin-1 beta; TNF-α: Tumor necrosis factor-alpha; MASLD: Metabolic dysfunction–associated steatotic liver disease.

Out of the neurobiological systems coordinated by neuroinflammation, dysregulation of the HPA axis and depletion of brain serotonin are the primary perpetrators for development of depression[17-20]. As mentioned earlier, MASLD may occur as a predictable outcome of obesity or even as a metabolic consequence of IR. Individuals that are overweight and obese have altered serum levels of proinflammatory cytokines such as TNF-α, C-reactive protein (CRP), IL (IL-6, IL-18)[132-134]. These cytokines are also crucial in the development of IR[55,66]. A vicious cycle exists between the inflammatory response in obesity and MASLD[135]. The severity of MASLD is exacerbated due to the failure of obesity induced inflammation to resolve[136]. What’s interesting to note is that, even though these same proinflammatory cytokines are definitely involved in the development of depression, some studies have proven that the association between MASLD and depression is independent of these metabolic and lifestyle risk factors such as obesity[25,34,137,138].

It is, however, worth mentioning that these metabolic risk factors accelerate vascular disease in MASLD patients which may result in brain atrophy[139-143]. Depression patients also show similar structural and functional neuroimaging findings namely, cortical thinning and reduced gray matter[144]. According to Colognesi et al[32], the significant reduction of white and gray matter in the brain suggests a higher risk of depression in MASLD diagnosed patients. This is supported by Filipović et al[145], who found that MASLD patients had significant reductions in brain volume and a higher risk of depression compared to controls. Ntona et al[146] further supports this claim by declaring that prefrontal cortex lesions occur in both depression and MASLD associated systematic hyperinflammatory state.

Reduced levels of nesfatin-1 and copine-6-associated brain-derived neurotrophic factor levels have also been considered as a probable link between MASLD and depression[147].

HPA axis hyperactivation: Stress-induced activation of the HPA axis plays a central role in maintaining homeostasis, but chronic hyperactivation has been implicated in both liver pathology and mood disorders[12]. In the context of MASLD, metabolic factors including IR, obesity, and systemic inflammation result in the hyperactivation of the HPA axis. This results in sustained cortisol secretion, which further promotes hepatic gluconeogenesis, fat accumulation, and lack of insulin sensitivity, resulting in the progression of hepatic steatosis[148-150]. Although glucocorticoids are classically anti-inflammatory, their prolonged elevation paradoxically enhances lipid deposition in hepatocytes and impairs mitochondrial function[151].

Simultaneously, multiple studies have proven that hyperactivity of the HPA axis is a well-established hallmark in major depressive disorder, suggesting that this shared neuroendocrine dysfunction might serve as a pathophysiological bridge between MASLD and depression[152-154]. A study expanding on the ‘emotional nervous system’ explained how the body weight of stressed individuals may be influenced by the HPA axis through cortisol regulation[155]. Prolonged cortisol elevation leads to hippocampal shrinkage (as mineralocorticoid receptors are localized to the hippocampus in the brain and cortisol binds to high affinity with these receptors), disrupting synaptic plasticity, and impairing serotonergic and dopaminergic neurotransmission—contributing to core symptoms of depression[156-158]. This desensitization occurs in both hepatocytes and the brain, impairing cortisol’s regulatory effects on inflammation and HPA axis feedback. In hepatocytes, glucocorticoid receptor (GR) desensitization weakens cortisol’s ability to suppress inflammatory cytokines like IL-6 and TNF-α, worsening hepatic inflammation[159]. In the hippocampus, chronic cytokine exposure reduces GR sensitivity, disrupts negative feedback on the HPA axis, and leads to sustained cortisol release[160,161].

Figure 2 shows how chronic HPA axis activation in MASLD raises cortisol levels, which disrupt serotonin and dopamine signaling in areas like the hippocampus[148-150]. It also shows how cortisol worsens steatosis, enhances gluconeogenesis, and worsens IR, linking metabolic dysfunction to emotional and cognitive changes[151].

Figure 2.

Hyperactivation of the hypothalamic–pituitary–adrenal axis in Metabolic dysfunction–associated steatotic liver disease: Metabolic and neuropsychiatric consequences. HPA: Hypothalamic–pituitary–adrenal; CRH: Corticotropin-releasing hormone; ACTH: Adrenocorticotropic hormone; BDNF: Brain-derived neurotrophic factor; MASLD: Metabolic dysfunction–associated steatotic liver disease.

While current understanding is evolving, pharmacologic interventions targeting HPA axis dysregulation have been explored in mood disorders. A meta-analysis by Ding et al[27] showed that certain HPA-modulating agents, such as GR antagonists, may benefit patients with major depression. However, inconsistent results across trials highlight the need for focused, head-to-head studies exploring this pathway.

Neurotransmitter imbalances: The liver plays a key role in tryptophan metabolism through the enzyme tryptophan 2,3-dioxygenase (TDO), which shifts tryptophan away from serotonin synthesis[162]. In MASLD, liver inflammation and oxidative stress impair this balance[163]. TDO activity becomes dysregulated and indoleamine 2,3-dioxygenase is increasingly activated by cytokines like IL-6 and TNF-α[164,165]. This leads to reduced serotonin availability in the brain. The resulting imbalance may affect mood and cognition. Animal studies have also shown disrupted dopamine and GABA signaling in MASLD-related neuroinflammation[166].

While hepatic dysfunction alters tryptophan metabolism, studies also show how gut microbial products particularly short-chain fatty acids (SCFAs) can influence brain inflammation and mood regulation. SCFAs such as acetate, propionate, and butyrate are generated through the microbial breakdown of dietary fibers. These SCFAs have been shown to cross the blood–brain barrier via monocarboxylate transporters and influence central nervous system activity[167]. Butyrate, in particular, can suppress microglial activation and exert anti-inflammatory effects by inhibiting histone deacetylases which ultimately protects the brain against neuroinflammation[167,168]. In individuals with MASLD, reduced SCFA production due to dysbiosis may impair this protective signaling hence promoting a pro-inflammatory state in the brain.

Apart from SCFAs, gut dysbiosis in MASLD can also affect tryptophan metabolism, which plays a key role in mood and brain inflammation. Under normal conditions, tryptophan is used as a precursor in serotonin synthesis in the brain. However in the context of MASLD, gut dysbiosis can push tryptophan into the kynurenine pathway[169]. This shift increases the production of neurotoxic metabolites such as quinolinic acid, which can cross the blood–brain barrier and promote oxidative stress, excitotoxicity, and microglial activation, factors known to contribute to depressive symptoms[170-174]. This shift is likely driven by gut dysbiosis in MASLD, which involves a loss of beneficial microbes and an overgrowth of pro-inflammatory ones. These microbial alterations are further detailed in the Gut dysbiosis section[175-178].

Gut dysbiosis: Emerging research continues to shed light on the intricate relationship between gut dysbiosis and MASLD, suggesting that disturbances in the gut microbiome might not only influence liver pathology but also contribute to mental health challenges. In individuals with MASLD, studies consistently report reduced microbial diversity, an increase in harmful pro-inflammatory bacteria such as Proteobacteria and Enterobacteriaceae, and a drop in beneficial species like Faecalibacterium prausnitzii[175,176]. Faecalibacterium prausnitzii supports gut health by producing butyrate, a SCFAs that reduces inflammation and maintains intestinal barrier integrity. In contrast, enterobacteriaceae are pro-inflammatory bacteria that release endotoxins like lipopolysaccharide (LPS), which trigger immune responses and worsen both hepatic and neural inflammation[176]. These changes are known to disrupt the intestinal barrier and trigger metabolic endotoxemia, which are the processes that aggravate inflammation and fat accumulation in the liver[179,180]. The disruption of bile acid metabolism in MASLD reduces microbial control, allowing harmful bacteria to thrive[181]. Combined with IR, which impairs gut integrity and immune responses, these factors significantly contribute to gut dysbiosis[182].

The disruption of bile acid metabolism in MASLD plays a more important role than it might initially seem. More than its role in aiding digestion, bile acids function as signaling molecules that help maintain microbial balance in the gut. Under healthy conditions, they exert antimicrobial effects that suppress the growth of harmful bacteria. In MASLD, bile acid synthesis and circulation become dysregulated, leading to an altered composition of the bile acid pool. This reduces their ability to regulate gut microbial populations, allowing pathogenic bacteria to grow invariably. One notable consequence is the overgrowth of gram-negative species such as Enterobacteriaceae, which can increase the release of endotoxins like LPS. These microbial products contribute to systemic inflammation and can exacerbate hepatic injury[181].

IR which is one of the hallmark features of MASLD further aggravates the problem. When insulin signaling is impaired, it affects more than just glucose and lipid metabolism. It also compromises gut epithelial integrity, increasing intestinal permeability, or what is commonly referred to as a “leaky gut”[182]. IR is also associated with impaired mucosal immunity, which reduces the host’s ability to control opportunistic pathogens. As a result, the combined effects of disrupted bile acid signaling and weakened immune defenses foster a persistent state of gut dysbiosis. Over time, this dysregulated gut–liver axis fuels a self-sustaining cycle of inflammation that drives disease progression and may even contribute to extrahepatic complications, including neuroinflammation[173,174].

But the gut’s influence doesn’t end with the liver. The gut-brain axis, a complex, two-way communication system between the central nervous system and the gastrointestinal tract is deeply influenced by the gut microbiota. Through the intricate neural, endocrine, and immune signaling pathways, these microbes can affect brain function and behavior[183-186]. For instance, Lactobacillus rhamnosus has been shown to reduce anxiety and depressive-like behavior in animal models through vagal nerve activation, highlighting the microbial impact on mood regulation[187]. Therefore, disruptions in the gut microbiome have been linked not only to liver dysfunction, as seen in MASLD, but also to increased vulnerability to anxiety and depression[177,178]. At the same time, through the gut-liver axis, the microbiome plays a crucial role in the onset and progression of MASLD. This reflects a deeply interconnected, bidirectional relationship between the gut, liver, and brain[175,188]. Figure 3 illustrates how gut dysbiosis in MASLD sets off a cascade of events. It begins with reduced microbial diversity, loss of helpful bacteria, and impaired fermentation of dietary fibers. This leads to lower SCFAs and disrupted bile acid metabolism[181]. A weakened gut barrier allows bacterial products like LPS to leak into the portal circulation, triggering hepatic inflammation. At the same time, dysbiosis shifts tryptophan metabolism toward kynurenine, a neurotoxic metabolite. These changes travel beyond the liver through systemic circulation, thereby activating the HPA axis and promoting microglial activation in the brain. This, in turn, contributes to anxiety and depression[168].

Figure 3.

Gut–liver–brain axis examining the association between metabolic dysfunction–associated steatotic liver disease and depression/anxiety. SCFA: Short-chain fatty acids; LPS: Lipopolysaccharides; BBB: Blood–brain barrier; BDNF: Brain-derived neurotrophic factor; GABA: Gamma-aminobutyric acid; MASLD: Metabolic dysfunction–associated steatotic liver disease.

A recent study by Madabushi et al[28] highlights the promising role of gut health in improving mental well-being. Their findings suggest that interventions aimed at modulating the gut microbiota particularly through the use of probiotics may help alleviate symptoms of anxiety and depression. These benefits are thought to arise from probiotics’ ability to reduce systemic inflammation, restore microbial diversity and influence key neurochemical pathways, including the production of serotonin and gamma-aminobutyric acid. The review highlights the increasing recognition of the gut-brain axis as a therapeutic target, suggesting that mental health should not be treated in isolation from gut health. While more high-quality clinical trials are needed to define specific strains and dosages, the emerging evidence paints a hopeful picture of microbiome-focused approaches in psychiatric care.

Hence, targeting the gut microbiota through dietary interventions, probiotics, or even fecal microbiota transplants (FMT) may not only help manage MASLD directly but also ease some of the mental health difficulties that often accompany the condition. Recent studies suggest that modulating the gut environment can reduce inflammation, support neurotransmitter production, and influence mood-regulating pathways in the brain. For example, Radford-Smith and Anthony[189] describe how probiotics and prebiotics may help regulate neuroinflammation and improve emotional resilience by supporting the microbiota–gut–brain axis. Similarly, Vaghef-Mehrabany et al[190] throw light on growing evidence from randomized trials that specific strains of probiotics and synbiotics may offer measurable antidepressant effects, particularly when personalized according to the individual.

CONCLUSION

MASLD and mood disorders frequently coexist, yet there are no exclusive biomarkers available to track their combined progression. However, several overlapping markers may hold clinical value. Elevated CRP, IL-6, and TNF-α reflect the chronic inflammatory state shared by both conditions. The kynurenine-to-tryptophan ratio reflects shunting of tryptophan into neurotoxic pathways, while reduced serum glutamine which is an important neurotransmitter precursor has also been reported in patients with comorbid depression[191,192]. These markers may help in early identification and risk stratification, but we still need studies to confirm their usefulness in hepatic and psychiatric clinics. Longitudinal studies are especially needed to confirm causality specifically, whether gut dysbiosis precedes both MASLD and mood disorders or results from them.

Microbiota-targeted therapies show a promising direction towards a dual benefit. Probiotics and FMT have shown modest improvements in hepatic inflammation, steatosis, and mood symptoms. These effects are thought to occur through restoration of SCFAs production, enhanced gut barrier function, and improved serotonin signaling. The HPA axis remains another emerging therapeutic target. Since the HPA axis plays a role in both MASLD and depression, drugs like mifepristone that were mentioned earlier could be explored in future dual-targeted trials. Looking ahead, multi-omic studies are essential to understand the gut-liver-brain axis in more detail. Recent work links glutamate-producing microbes like Anaerotruncus colihominis to mood symptoms in metabolic disease[193,194]. Trials should also consider sex-specific factors like gut composition, hormonal regulation, and immune response. Alongside microbial and pharmacologic options, lifestyle changes remain crucial. Regular physical activity improves liver fat and reduces depressive symptoms by regulating stress pathways. Anti-inflammatory diets can enhance both mood and metabolic outcomes by supporting glucose control, lowering inflammation, and restoring gut microbial balance. A holistic care model including early psychiatric screening and regular monitoring using overlapping biomarkers will be beneficial. Dual-targeted treatment strategies addressing both liver and mental health may offer the most effective approach for improving long-term outcomes.