Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide, affecting approximately 35% of the global adult population. Its prevalence has increased by nearly 50% since the 1990s^{[1, 2]}. NAFLD encompasses a broad spectrum of hepatic conditions, ranging from simple steatosis to more advanced forms such as non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC)^{[3, 4]}. Beyond liver pathology, NAFLD is strongly associated with extrahepatic comorbidities, including cardiovascular disease, type 2 diabetes, chronic kidney disease, and increased risk of premature mortality^{[5, 6]}.

Recently, the term NAFLD has been redefined as metabolic dysfunction-associated fatty liver disease (MASLD) to better reflect its integration within systemic metabolic dysfunction^[7]. The pathogenesis of MASLD is multifactorial, and inflammation is central to both its initiation and progression. Systemic inflammation exacerbates metabolic dysfunction and accelerates the progression from simple steatosis to more advanced conditions such as NASH and cirrhosis. It is also involved in the development of comorbidities commonly observed in MASLD, including cardiovascular disease and diabetes.

Several composite inflammatory indices have been developed to provide a nuanced assessment of inflammatory activity. These include the Inflammatory Burden Index (IBI), Systemic Inflammation Response Index (SIRI), Aggregate Index of Systemic Inflammation (AISI), and Remnant Cholesterol Inflammatory Index (RCII), each combining multiple biomarkers to provide a comprehensive understanding of systemic inflammation and its impact on disease progression^[8–11].

The IBI incorporates markers such as white blood cell count and C-reactive protein (CRP), which provide an overall measure of inflammatory burden. These markers are consistently elevated across inflammatory states and are useful in assessing MASLD severity^[12]. The SIRI, based on neutrophil, monocyte, and lymphocyte counts, reflects the balance between pro- and anti-inflammatory immune cells and has been investigated as a prognostic marker in several diseases, including MASLD, where shifts in immune cell ratios are linked to disease progression^[13]. The AISI includes neutrophil, monocyte, lymphocyte, and platelet counts, with particular focus on the inflammatory processes involved in atherosclerosis. Since cardiovascular disease is a major comorbidity in MASLD, the AISI is particularly relevant, as it reflects both the systemic inflammation involved in MASLD and the associated cardiovascular risk^[14]. The RCII, a relatively recent index, incorporates remnant cholesterol (RC), which is the difference between total cholesterol (TC) and the cholesterol carried by high-density and low-density lipoproteins. This index reflects systemic inflammation and accounts for lipid metabolism, which plays an essential role in MASLD pathogenesis. Given the prominent role of lipid dysregulation in MASLD, RCII provides a novel perspective on the intersection of lipid metabolism and inflammation in this disease^[15].

These indices have demonstrated significant associations with the prognosis of MASLD and other chronic conditions, indicating their potential value for identifying individuals at high risk of progression. However, the mechanisms linking these markers to MASLD are not fully understood. Important questions include the molecular pathways of inflammation-driven hepatic steatosis and fibrosis, the causal role of systemic inflammatory states, and the heterogeneity across different populations. Further investigations are needed to clarify the complex relationships between inflammation and MASLD and to confirm the utility of these indices as biomarkers for MASLD diagnosis and prognosis.

This study aimed to examine the relationships between four composite inflammatory indices (IBI, SIRI, AISI, RCII) and MASLD based on data from the National Health and Nutrition Examination Survey (NHANES, 1999–2010). NHANES, conducted by the Centers for Disease Control and Prevention (CDC), provides comprehensive health and lifestyle data from a representative sample of the U.S. population. Using this dataset, the study examined how these composite inflammatory indices correlate with MASLD and its progression, with the aim of clarifying the role of systemic inflammation and its potential as a target for future prevention and treatment strategies.

This study examined the relationships between four composite inflammatory indices (IBI, SIRI, AISI, and RCII) and MASLD using 1999–2010 NHANES data. The findings revealed the significant role of systemic inflammation in the pathogenesis of MASLD and the robust associations between these inflammatory markers and MASLD risk. These results provide a deeper understanding of the molecular mechanisms underlying MASLD and its implications for public health and clinical applications.

MASLD is closely tied to systemic metabolic dysfunction, including obesity, insulin resistance, and dyslipidemia. At the molecular level, these disruptions trigger inflammatory responses that contribute to liver damage and fibrosis progression^{[26, 27]}. Recent research supports the role of chronic low-grade inflammation in the development and progression of MASLD. Consistent with previous reports, our results indicate that elevated levels of inflammatory indices—IBI, SIRI, AISI, and RCII—are linked to increased MASLD risk^{[13, 28]}.

The inflammatory response in MASLD is driven by the activation of several molecular pathways, including the nuclear factor kappa B (NF-κB) pathway; inflammasome signaling; and the upregulation of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and CRP^{[29, 30]}. These mediators can exacerbate insulin resistance, adipocyte dysfunction, and hepatic lipogenesis, thereby accelerating the progression from simple steatosis to NASH and, eventually, cirrhosis^[31]. Our findings show that markers such as the IBI, which combines the CRP level and the neutrophil-to-lymphocyte ratio, reflect the extent of this inflammatory burden. This aligns with the findings of molecular evidence linking these markers to different stages of MASLD progression^[3].

In addition, our analysis revealed sex-specific differences. Both stratified analyses and RCS curves indicated that the association between RCII and MASLD was stronger in female participants than in male participants. This observation is consistent with previous reports that sex hormones, body fat distribution, and lipid metabolism differ by sex, thereby modifying the influence of dyslipidemia and systemic inflammation on hepatic steatosis^[32]. Women may experience distinct metabolic and hormonal effects, including the protective role of estrogen on lipid regulation and inflammatory pathways before menopause, whereas men are more likely to exhibit visceral adiposity and higher remnant cholesterol levels^[33]. These differences may help explain the stronger RCII–MASLD association observed in women in our study.

Moreover, indices that combine lipoprotein metabolism markers, such as the AISI and RCII, highlight the importance of lipid dysregulation in MASLD. Elevated LDL-C and TG, in addition to decreased HDL-C, are characteristic of metabolic syndrome and are closely associated with increased hepatic fat accumulation^[34]. The role of RC, captured by the RCII, further highlights the intricate relationship between lipid metabolism and inflammation, both of which contribute to liver injury and an increased risk of cardiovascular comorbidities in MASLD^[35].

MASLD is now recognized as the most common liver disease worldwide, affecting an estimated 25–30% of the global population, with prevalence rising steadily, particularly among individuals with obesity and type 2 diabetes^{[36, 37]}. This growing burden has considerable public health implications, given its association with cardiovascular diseases, diabetes, and chronic kidney disease^[38]. Our findings reinforce the importance of identifying early inflammatory markers to predict the onset and progression of MASLD, thereby supporting the development of targeted preventive and therapeutic strategies.

Given the systemic nature of MASLD, public health interventions should address broader metabolic dysfunctions that contribute to disease development. Lifestyle modifications, including weight reduction, dietary changes, and regular physical activity, are the cornerstone of MASLD prevention and management^{[39, 40]}. Moreover, our findings suggest that the IBI, SIRI, AISI, and RCII may be valuable for early detection and risk stratification, enabling healthcare providers to identify high-risk individuals before the onset of advanced hepatic injury. Integrating these markers into routine clinical practice could substantially enhance population-level management of MASLD and reduce the burden of liver-related morbidity and mortality^[41].

In clinical settings, these composite inflammatory indices may serve as non-invasive biomarkers for monitoring disease progression in individuals with MASLD. Although liver biopsy remains the gold standard for diagnosing NASH and staging fibrosis, it is invasive, costly, and prone to sampling errors^[42]. Non-invasive tests such as liver elastography and serum biomarkers are increasingly used, but further validation of inflammatory indices as diagnostic tools is necessary. Our study suggests that IBI, SIRI, AISI, and RCII could complement or, in some contexts, substitute for existing tests, thereby offering a more comprehensive assessment of the systemic inflammation underlying MASLD^[43].

The predictive models developed in this study using machine learning algorithms, particularly XGBoost, further demonstrated the potential of these inflammatory markers in assessing MASLD risk. Integrating clinical, demographic, and inflammatory data into robust predictive models could improve diagnostic accuracy and inform personalized therapeutic interventions. Nevertheless, prospective studies in larger and more diverse populations are needed to validate these findings and optimize the models for clinical use^[23].

Taken together, the RCII emerged as the most informative of the four inflammatory indices (IBI, SIRI, AISI, and RCII). In conventional analyses, RCII demonstrated the strongest and most consistent association with MASLD, with effect estimates remaining stable across sensitivity analyses. Likewise, machine learning comparisons consistently ranked RCII among the top predictors, and SHAP analyses highlighted its substantial global contribution alongside its localized effects on individual risk predictions. Biologically, this is plausible because the RCII integrates RC (a TG-rich, ApoB-containing fraction linked to hepatic lipid accumulation) with CRP (a systemic inflammatory marker). This combination allows RCII to capture the metabolic–inflammatory burden more directly than leukocyte-based composites^[44]. Clinically, these findings suggest that the RCII may serve as a practical, integrative biomarker to refine MASLD risk stratification beyond traditional lipid parameters and cell-count indices.

While our study provides valuable insights, several limitations should be addressed in future research. First, the cross-sectional nature of the NHANES data precluded the establishment of causal relationships between inflammation and MASLD. Longitudinal studies are needed to determine whether elevated inflammatory indices precede the onset of MASLD or occur as a consequence of the disease^[45]. Second, while our analysis adjusted for several potential confounders, unmeasured factors may still have influenced the relationship between inflammation and MASLD. For instance, genetic predisposition, gut microbiota composition, and environmental exposures may all contribute to the disease’s development and progression^[46]. Future studies should incorporate these variables to provide a more comprehensive understanding of the molecular mechanisms underlying MASLD.

Furthermore, while we focused on four inflammatory indices, other biomarkers of immune dysregulation and metabolic dysfunction, such as adipokines and oxidative stress markers, were not included. Investigating the interplay between these additional markers and the indices studied here could reveal novel insights into MASLD pathogenesis and help enhance risk prediction models^[47]. Finally, the external validity of our findings would be improved by including more diverse populations, particularly from regions outside the U.S., where dietary habits, lifestyle factors, and genetic predispositions may differ.

This study highlighted the significant role of systemic inflammation in the development and progression of MASLD and demonstrated the potential of inflammatory indices as biomarkers for early diagnosis and risk stratification. The mechanisms underlying these associations suggested that therapeutic strategies targeting inflammation and lipid dysregulation may hold promise in MASLD management. At the population level, public health efforts should prioritize lifestyle interventions to mitigate the rising prevalence of MASLD, while in clinical settings, incorporation of these indices could enhance patient stratification and outcomes. Despite some limitations, our findings provide a foundation for future research into non-invasive diagnostic tools and personalized treatment strategies for MASLD, ultimately contributing to the broader goal of reducing the global burden of metabolic liver disease.