The present systematic review synthesizes the current evidence on the association between MASLD and a broad spectrum of respiratory disorders. Overall, the available literature suggests that MASLD may be linked to several pulmonary conditions, including COPD, asthma, OSA, interstitial lung disease, pulmonary hypertension, and respiratory mortality [14,15,16,17,18, 22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]. Notably, although bronchiectasis was included among the predefined outcomes of interest, no eligible studies specifically addressing this condition were identified, highlighting an important gap in the current literature.

The strength and consistency of the evidence vary substantially across respiratory phenotypes. While the association appears more consistently supported for some conditions, particularly COPD and OSA, findings for other disorders remain more heterogeneous and less conclusive [14,15,16,17,18, 22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]. Importantly, the interpretation of these associations should be considered in the context of study quality. The most consistent and robust findings, particularly for COPD, OSA, and composite respiratory outcomes, are primarily supported by large population-based cohort studies and analyses derived from nationwide datasets, many of which were assessed as having low to moderate risk of bias. These studies typically incorporated extensive multivariable adjustment and large sample sizes, enhancing the reliability of their findings. In contrast, evidence derived from smaller clinical cohorts or highly selected populations, including sleep clinic or bariatric surgery cohorts, as well as cross-sectional analyses, should be interpreted more cautiously due to moderate risk of bias, potential selection bias, and the absence of temporal inference. Notably, no cross-sectional study was classified as unequivocally low risk of bias, reflecting inherent limitations of this design. MR studies, although methodologically rigorous, yielded inconsistent results across respiratory outcomes, further highlighting the complexity of the observed associations.

The interpretation of MR findings in this context requires particular caution. Although MR offers an approach to strengthen causal inference by leveraging genetic instruments, its validity depends on key assumptions, including the absence of horizontal pleiotropy and the appropriate selection of instrumental variables. In the included studies, MR results were not consistent across respiratory outcomes and appeared sensitive to analytical choices, such as adjustment for obesity-related traits and the handling of pleiotropic variants. In several analyses, initially significant associations were attenuated after sensitivity analyses or exclusion of outlier instruments, suggesting that shared genetic determinants, particularly those related to adiposity and metabolic dysfunction, may partly account for the observed relationships. Furthermore, variation in phenotype definitions (e.g. questionnaire-based versus polysomnography-defined OSA) may introduce additional heterogeneity. Therefore, MR findings should be interpreted as supportive but not definitive evidence of causality, and should be considered alongside observational and mechanistic data.

An additional important source of heterogeneity relates to the use of different diagnostic frameworks for steatotic liver disease, including NAFLD, MAFLD, and MASLD. Although these terms are often used interchangeably in the literature, they are not fully equivalent. NAFLD is defined by the exclusion of secondary causes of hepatic steatosis, whereas MAFLD and MASLD adopt a positive definition based on the presence of metabolic dysfunction. In particular, MAFLD criteria may preferentially identify individuals with a higher cardiometabolic burden, potentially enriching study populations for systemic inflammation and metabolic comorbidity. As a result, studies using MAFLD definitions may report stronger associations with respiratory outcomes compared to those using NAFLD criteria. Conversely, NAFLD-based definitions may include more heterogeneous populations, including individuals without overt metabolic dysfunction. These differences may contribute to variability in effect estimates, limit comparability across studies, and introduce potential misclassification when synthesizing evidence. Importantly, in the present review, all diagnostic terms were retained as originally defined in the included studies, and findings were interpreted within the context of these evolving definitions.

Although heterogeneity across study designs and diagnostic definitions precluded quantitative synthesis, several important patterns emerge. First, MASLD appears highly prevalent among patients with COPD and OSA, and its presence is associated with more severe respiratory phenotypes in several cohorts [14, 15, 17, 31]. While shared risk factors such as obesity and smoking contribute to this overlap, most large cohort studies adjusted for major metabolic and lifestyle confounders, including BMI, smoking status, age, sex, diabetes, hypertension, dyslipidemia, alcohol intake, and, in some datasets, markers of insulin resistance and systemic inflammation. Notably, the associations between MASLD and respiratory outcomes persisted after multivariable adjustment, suggesting that qualitative adipose tissue dysfunction, often referred to as “meta-inflammation”, and hepatokine-mediated signaling may exert effects beyond simple somatometric indices of obesity. Importantly, several population-based studies demonstrate that this relationship remains significant after adjustment for traditional metabolic confounders [18, 22,23,24], supporting the concept that hepatic steatosis may reflect an active component of systemic metabolic dysfunction rather than a passive epiphenomenon.

Second, the relationship between liver disease and lung function extends beyond simple comorbidity. Evidence suggests that hepatic fibrosis, in particular, may be linked to functional impairment, including reduced lung volumes and peripheral airway dysfunction [25, 26]. These findings support the hypothesis that progressive liver injury, rather than isolated steatosis, may contribute to systemic inflammatory and fibrotic signaling that impacts pulmonary structure and function. Advanced fibrosis may represent a cumulative index of chronic metabolic stress, integrating adipose tissue–derived inflammatory signaling, oxidative injury, and sustained activation of profibrotic pathways, notably TGF-β signaling [47, 48].

In addition to classical cytokine-mediated inflammation, emerging data support a role for hepatokine-mediated interorgan communication within the liver–lung axis. Hepatokines, such as fibroblast growth factor 21 (FGF-21), fetuin-A, and angiopoietin-like proteins are dysregulated in MASLD and may modulate systemic insulin sensitivity, endothelial function, and inflammatory tone [9, 11]. Although FGF-21 is initially considered a compensatory metabolic hormone, persistent elevation may reflect metabolic stress and has been linked with fibrotic remodeling and oxidative pathways [9,10,11]. Moreover, platelet-derived growth factor (PDGF) signaling, a central driver of hepatic stellate cell activation and fibrogenesis, shares profibrotic downstream cascades with pulmonary fibroblast activation, including TGF-β–mediated extracellular matrix deposition. These shared hepatokine and growth factor pathways provide a plausible mechanistic substrate for parallel hepatic and pulmonary fibrotic remodeling beyond simple obesity-related inflammation [9, 11]. In asthma, associations appear more closely related to shared metabolic and inflammatory dysregulation rather than direct hepatic injury per se [16, 18, 28]. Moreover, in obesity-associated asthma phenotypes, leptin-mediated airway hyperresponsiveness, reduced adiponectin signaling, and systemic IL-6 activation may amplify airway inflammation, providing a plausible biological bridge between hepatic steatosis and asthma risk [49].

Third, the MASLD–OSA relationship is among the most robust and biologically plausible associations identified [17, 31,32,33,34,35,36,37]. Chronic intermittent hypoxia, a hallmark of OSA, is known to promote hepatic lipid accumulation, oxidative stress, and fibrogenesis. Conversely, obesity, systemic inflammation and metabolic dysfunction in MASLD may predispose to upper airway collapsibility and OSA development. Nevertheless, MRS have yielded inconsistent results, particularly after adjustment for BMI, suggesting that chronic low-grade inflammation and insulin resistance remain major drivers of the observed epidemiological overlap [35,36,37]. This inconsistency likely reflects the complex interplay between obesity, upper airway mechanics, intermittent hypoxia, and hepatic lipid metabolism, rather than a simple unidirectional causal pathway.

The association between MASLD and interstitial lung disease, including IPF, is an emerging area of research interest [15, 35]. Converging mechanistic data indicate shared profibrotic pathways involving TGF-β signaling, oxidative stress, lipid metabolic reprogramming, and extracellular matrix remodeling [50,51,52,53,54]. Moreover, obesity-related mitochondrial dysfunction, altered fatty acid oxidation, and extracellular matrix remodeling may further contribute to a systemic profibrotic milieu affecting both hepatic and pulmonary parenchyma [55]. These parallels support the concept of a systemic fibrotic predisposition in metabolically dysregulated states, although clinical evidence remains limited and requires prospective validation.

At the advanced disease spectrum, pulmonary vascular complications further illustrate the clinical relevance of the liver–lung axis. PoPH represents a severe complication of advanced liver disease, and emerging data suggest that even early pulmonary hemodynamic alterations may influence prognosis. These findings underscore the systemic vascular and thrombo-inflammatory burden associated with metabolic and fibrotic liver disease [27, 28].

Overall, the findings may support a metabolically mediated liver–lung axis. MASLD should therefore be considered not only a metabolic comorbidity but potentially a modifier of respiratory disease risk and phenotype. Within this model, MASLD may function less as an isolated hepatic disease and more as a measurable manifestation of systemic adipose tissue dysfunction, reflecting the intensity of metabolic stress imposed on multiple organ systems.

From a clinical perspective, weight reduction represents a shared therapeutic target across several conditions. The Global Initiative for Asthma (GINA) recommends that weight reduction should be included in the treatment plan for patients with obesity and asthma (Evidence level B), noting that even 5–10% weight loss may lead to improved asthma control and quality of life, with the most striking results observed after bariatric surgery [56].

Evidence further indicates that metabolic improvement through lifestyle or bariatric interventions may favorably influence asthma control [57], reinforcing the interconnected nature of hepatic and pulmonary metabolic dysregulation. Figure 2 summarizes the liver–lung axis in MASLD.

The liver–lung axis in MASLD. MASLD promotes systemic metabolic and inflammatory dysregulation characterized by insulin resistance, oxidative stress, hepatokine imbalance, and pro-fibrotic signaling. Circulating inflammatory cytokines, hypoxia-inducible pathways, endothelial dysfunction, and extracellular matrix remodeling contribute to airway inflammation, small airway dysfunction, interstitial fibrosis, and pulmonary vascular remodeling. Conversely, pulmonary disorders, particularly obstructive sleep apnea, induce intermittent hypoxia and systemic oxidative stress that may accelerate hepatic steatosis progression and fibrogenesis

To provide an at-a-glance synthesis across respiratory phenotypes, Fig. 3 presents a qualitative forest-style summary of the reported associations between MASLD and each major respiratory disorder. This is not a formal meta-analysis; however, it summarizes the direction of association and the relative consistency of findings across the included adjusted human studies in the presence of substantial clinical and methodological heterogeneity.

Qualitative forest-style summary of associations between MASLD and major respiratory disorders. Interpretation: Points to the right of the null line indicate that the majority of included studies report an increased risk/prevalence of the respiratory disorder among individuals with MASLD; points near the null line indicate mixed or inconclusive results. Larger points denote higher consistency and stronger supporting evidence (based on number/size of adjusted cohort studies and concordance of direction), while smaller points indicate limited evidence. This visualization is intended as an overview of the evidence and should not be interpreted as a pooled effect estimate

Importantly, while many associations are consistent and biologically plausible, causality remains uncertain. MRS have not consistently confirmed direct causal effects for COPD or asthma [25, 30,31,