Nonalcoholic fatty liver disease (NAFLD) stands as the predominant cause of chronic liver disease on a global scale, affecting approximately 25% of the world’s population (1, 2). Manifesting in a spectrum of pathological features, NAFLD ranges from simple intrahepatic lipid accumulation, characterized by steatosis and non-alcoholic fatty liver (NAFL), to the progression of non-alcoholic steatohepatitis (NASH), encompassing varying degrees of necrotizing inflammation, accelerated fibrosis, cirrhosis, and ultimately hepatocellular carcinoma (HCC) (3, 4). Driven by shifts in dietary patterns, lifestyle choices, and an aging population, the incidence of NAFLD is on the rise, emerging as a pervasive global health concern (5). Beyond its impact on liver function, research has elucidated a significant association between NAFLD and cardiovascular disease (CVD). Notably, NAFLD has been identified as an independent risk factor for the onset of CVD, a leading contributor to global of morbidity and mortality (6, 7).

Currently, no pharmaceuticals are specifically endorsed for the treatment of NAFLD, making lifestyle modification and the management of risk factors the foremost therapeutic approach for patients with NAFLD (8). Consequently, antioxidant-based dietary and lifestyle interventions have attracted attention as potential strategies to diminish the risk of NAFLD progression and related complications. Despite an incomplete understanding of NAFLD’s pathogenesis, numerous studies have emphasized the pivotal role of oxidative stress, stemming from an imbalance in oxidative and antioxidant processes, in the initiation and progression of NAFLD (9–11). Dietary and lifestyle adjustments rich in antioxidants, such as regular exercise and smoking cessation, have been proposed (12). Research (13–15) has indicated that various antioxidants, including vitamin E and polyphenolic compounds, can ameliorate NAFLD/NASH by inhibiting lipid oxidation and accumulation. These interventions aim to modulate reactive oxygen species, consequently alleviating oxidative stress, improving liver function, and reducing liver-related morbidity and mortality.

While numerous studies have explored the impact of antioxidant diets and lifestyles on liver-related outcomes, the relationship between these interventions and the prevalence of CVD and mortality in adult NAFLD patients remains understudied. Thus, our investigation was based on data from the US National Health and Nutrition Examination Survey (NHANES) combined with the OBS assessment tool to understand the association and potential benefits of antioxidant diets and lifestyles in the prevalence of CVD and mortality among NAFLD patients. We aim to mitigate the disease burden and improve outcomes in this population.

Our investigation encompassed 8,670 eligible participants diagnosed with NAFLD. Utilizing the comprehensive indicators of oxidative stress, specifically the OBS, we sought to elucidate how dietary and lifestyle factors, when adjusted within the practical context of prevalence and mortality of CVD in individuals with NAFLD.

The “Multiple hit” hypothesis currently stands as a fitting framework to elucidate the pathogenesis of NAFLD. Among various contributing factors, oxidative stress emerges as a primary instigator of injury and disease progression in NAFLD (24). Elevated generation of reactive oxygen species (ROS), in particular, exerts influence on hepatic lipid metabolism reprogramming, alterations in insulin sensitivity, and modulation of inflammation through interaction with innate immune signaling (25). Intriguingly, NAFLD and CVD share common risk factors, such as obesity, insulin resistance, and type 2 diabetes mellitus. Several studies have identified shared pathophysiological pathways between the two, with oxidative stress serving as a pivotal link. In the context of NAFLD, characterized by chronic inflammation, mitochondrial dysfunction, endoplasmic reticulum stress, and disrupted lipid metabolism are probable, collectively contributing to heightened cellular oxidative stress. This, in turn, triggers systemic inflammation, thrombosis, hypertension, and endothelial dysfunction, thereby instigating and propelling the onset and progression of CVD (26–29). Furthermore, clinical observation indicate that incorporating dietary antioxidants (including vitamin E, vitamin C, caffeine, coffee polyphenols, and hesperetin), along with lifestyle interventions like regular exercise, may enhance the prognosis of NAFLD in individuals with a heightened cardiometabolic risk, exerting beneficial effects through the modulation of oxidative stress (30). This is consistent with the results of our study. Our findings show that higher OBS quartiles show consistent associations with lower CVD prevalence across cardiovascular subtypes, underscoring the potential protective effects of an antioxidant rich diet and lifestyle choices in individuals with NAFLD. Additionally, we observed a linear relationship between overall OBS and the prevalence of CVD in NAFLD patients, underscoring the role of oxidative stress in the pathogenesis of CVD and emphasizing the importance of antioxidant interventions to mitigate oxidative damage. Furthermore, our observations suggest a potential does-response relationship, signifying that greater adherence to an antioxidative diet and lifestyle is associated with more substantial reductions in CVD prevalence within this population.

An interesting finding emerged from our investigation into the relationship between specific types of CVD and OBS: while lifestyle OBS exhibited an association with reduced risks of CHF and heart attack, dietary or overall OBS did not demonstrate such associations. Several factors may ecaudate this phenomenon. Firstly, known risk behaviors such as smoking and excessive alcohol intake contribute to the development of CHF and heart attack. Secondly, physical activity can positively impact heart function, blood pressure, and improve cholesterol levels (31). Furthermore, research indicates a potential dose–response relationship between elevated BMI and the risk of heart failure (32, 33). These factors, individually or synergistically, may directly influence cardiac health. Due to the necessity for efficient utilization of ingested nutrients by the body, influenced by individual variations in bioavailability and metabolism, a study assessing the bioavailability of iron, zinc, protein, and vitamin A in each diet of French adults revealed significant variability across individual dietary patterns (34). Consequently, in contrast to lifestyle factors, the impact of independent dietary OBS on specific types of CVD may manifest as more indirect and intricate. Secondly, CHF and heart attack often result from long-term CVD progression, whereas dietary habits may primarily affect heart health at a preventive or early stages. For instance, studies suggest that modest daily vitamin D and calcium supplementation may prevent CHF in postmenopausal women without prior CVD. However, such supplements were found to have no discernible effect in postmenopausal women with existing CVD (35). Although these supplements are also considered antioxidants within dietary OBS. In addition, psychosocial factors may also contribute to these outcomes (36).

While our findings align with prior research indicating the protective impact of antioxidants on NAFLD/CVD, the longitudinal correlation of OBS utilization with all-cause and CVD mortality has yet to be comprehensive investigated and substantiated in individuals with NAFLD. At present, most of the literature review is a diet or lifestyle impact on CVD/independent of NAFLD. For instance, the American Heart Association has introduced the concept of ideal cardiovascular health, encompassing seven metrics that require monitoring over time (37). Four lifestyle behaviors (BMI, smoking, diet, and physical activity) have demonstrated an inverse association with CVD and total mortality across diverse populations, including Chinese, Spanish, and other countries, and multi-ethnic groups (38, 39). Notably, recent study has revealed that leisure and transport-related physical activity (≥150 min/week) exerts a protective effect on all-cause and CVD mortality in patients with NAFLD (40). Physical activity constitutes a component of an antioxidant lifestyle. However, the impact of a singular factor on the entire oxidation/antioxidant system is limited, and OBS provides a comprehensively assessment of an individual’s overall REDOX status by capturing diverse dietary and lifestyle factors (41). Recent studies have further demonstrated the correlation between OBS and various disease, indicating that higher OBS levels can decrease periodontitis and reduce the risk of colorectal cancer, and it can improve the symptoms of sleep disorder and depression (42–45). In our study, OBS was considered both as continuous and categorical variables adjusting for all relevant confounders. In fully adjusted models, each incremental unit in diet OBS, lifestyle OBS, and overall OBS demonstrated a 2, 7, and 2% decrease in all-cause mortality, respectively, among NAFLD patients. This indicates a correlation between higher OBS and reduced all-cause mortality. Diet and overall OBS exhibited associations with decreased CVD mortality, suggesting their potential significance and positive impact on preventing CVD-related death in NAFLD patients. Furthermore, RCS analysis supported a linear relationship, showing that all OBS were linearly associated with CVD and all-cause mortality in NAFLD patients overall. However, overall OBS showed a nonlinear association with all-cause mortality, possibly suggesting a saturation point for behaviors combining an antioxidant diet and lifestyle, beyond which additional protective effects may not accrue. Additionally, different analytical methods may demonstrate varying sensitivities to different data patterns and trends. These findings underscore the need for more individualized consideration in developing prevention and intervention strategies for NAFLD patients, with future studies warranted to delve deeper into related mechanisms. In conclusion, in the absence of approved pharmacologic treatments for NAFLD, diet and lifestyle remain pivotal, and antioxidant factors show potential protective effects in this context (46).

In addition, our study explored cancer mortality in NAFLD, extrahepatic malignant tumors and HCC as prevalent causes of death in NAFLD patients, alongside CVD (47). Our findings revealed that lifestyle Q2 and Q3 were linked to reduced cancer mortality, whereas diet and overall OBS did not exhibit an association. Notably, lifestyle OBS demonstrated a nonlinear associated with cancer mortality. A prior NHAENS-based study indicated that high diet quality was associated with reduced levels in non-NAFLD population, but this association was not observed in NAFLD patients. Diet quality was assessed using the Healthy Eating Index (HEI) score (48). This contrasts with numerous previous studies highlighting the beneficial effects of diet and lifestyle on cancer-related mortality in individuals without NAFLD (49). However, cancer mortality in individuals with NAFLD may be influenced by specific lifestyle factors, and this association might vary based on cancer type. Studies have shown that aerobic exercise is negatively correlated with breast cancer and colorectal cancer mortality, but the mortality associated with liver cancer is more common in patients with NAFLD (50, 51).

Remarkably, in our stratified analyses, age (< 45 years) and education level (> high school) emerged as significant factors influencing association between OBS and CVD prevalence. Educational level also exerted a significant impact on the protective effect of OBS against all-cause and CVD mortality. There exists statistical evidence suggesting that as individuals reach the middle age of their biological lifespan, various pathological consequences start interfering with the cardiovascular system and metabolic processes. Notably, aging is intricately linked to oxidative stress, aligning with the “Free Radical Theory of Aging” proposed by D. Harman in the mid-1950s, highlighting increased reactive ROS production as a key aging factor (52). Aging-related dysregulation of hepatic lipid metabolism is mediated by disruption in nutrient sensing, mitochondrial dysfunction, autophagy, and the presence of senescent cells, playing a pivotal role in NAFLD-HCC progression (53). We hypothesize that younger individuals benefit more from an antioxidant diet due to their faster metabolic rate, enhanced digestion, and absorption capacity, which facilitates better management of the ROS generated during metabolism. Conversely, older adults exhibit slower metabolism, compromised liver function, reduced intestinal absorption, and immunosenescence (54). Furthermore, reliance on self-reported dietary data in our study presents unique challenges, particularly among older individuals. Cognitive decline and memory impairment in this demographic may have influenced responses to dietary questionnaires, potentially contributing to variations in outcomes (55). Nevertheless, initiating an antioxidant-rich diet and lifestyle from a younger age remains paramount for the prevention and management of NAFLD. Intriguingly, unlike CVD, the modifying effect of age on cancer mortality was more pronounced at the age of ≥45 years and < 60 years in dietary OBS. Firstly, as individuals age, notable changes occur in the body’s endocrine and immune systems. Moreover, different types of cancer exhibit variable incidence and mortality across age groups. For instance, an analysis of surveillance data on cancer mortality in China from 2005 to 2020 indicated that the top three fatal cancer among men and women aged 40–59 years were liver, tracheal, and bronchial cancers, whereas leukemia was the predominant cause of cancer-related death in the 0–19 year age group (56). This aligns with our findings, given that liver cancer is one of the leading causes of death in the NAFLD population (47). Thus, our results underscore the complexity of how various diseases respond to age and dietary influences. In addition, our findings consistently demonstrated that for both dietary and lifestyle OBS, possessing an education level exceeding high school was invariably linked with a reduced risk of diseases and mortality. A study indicated that each 4.2-year increase in education causally predicted a 52% reduction in NAFLD prevalence. Higher education levels correlate with increased awareness of the link between a healthy diet, physical activity, and reduced risk of chronic disease. This heighted awareness promotes the acquisition of health knowledge and the ability to adhere to health behavior, indirectly reducing morbidity and mortality. Education level, a crucial determinant of socioeconomic status, profoundly influences the prevalence of chronic diseases, often shaping an individual’s career tracery and income prospects (57). Given the considerable global disparities in education (58), addressing educational inequality holds significant implications, particularly in light of the protective role of education beyond high school as identified in this study among the NAFLD population. Enhanced educational opportunities not only foster broader health literacy but also empower individuals to adopt healthier behaviors and lifestyles. Consequently, this holistic approach can mitigate the risk of NAFLD and CVD, optimize healthcare resources allocation, and alleviate the burden on healthcare systems. Therefore, tackling educational disparities stands as a pivotal stride toward enhancing health management and advancing public health on a broader scale (59). However, we noted the lack of a significant interaction between these two factors and disease in lifestyle OBS. This may be because lifestyle factors themselves have a direct and strong impact on the risk of disease, an effect that remains relatively stable across different ages and educational level. Moreover, the characteristics of the sample and limitations of statistical methods might also affect the results.

In fact, several healthy dietary approaches, including the Dietary Approaches to Prevent Hypertension (DASH), Dietary inflammation Index (DII), high-protein diet, intermittent calorie restriction diet, and Mediterranean diet (MED), have demonstrated associations with a reduced risk of NAFLD/CVD (60–62). It is crucial to emphasize that these dietary patterns are not uniform, and specific dietary recommendations may vary based on individual conditions and specific health goals. Beyond dietary patterns, other factors such as regular physical exercise, maintaining a healthy weight, and smoking cessation equally played an equally important role. However, our research findings not only underscore the pronounced oxidative characteristics of adopting healthy dietary and lifestyle habits in NAFLD but also highlight the associated of prevalence and mortality of CVD in NAFLD patients. In the realm of oxidative stress, independent or combined adherence to healthful diet and lifestyle continues to exhibit a significant capacity to diminish the risk of disease and its progression.

This study boasts several notable strengths. Utilizing data from the nationally representative NHAENS database spanning from 1999 to 2018, the inclusion of large samples and long-term tracking enhance the study’s external validity, offering relatively comprehensive and common samples. Large-scale data facilitate the identification of differences across various subpopulations and yield more robust statistical outcomes. The incorporation of diverse statistical methods enriches study’s comprehensiveness, allowing for a multifaceted exploration of associations. However, certain limitations warrant acknowledgment. Firstly, the reliance on self-reported data from respondents introduces the potential for information bias, especially in the assessment of antioxidant diet and lifestyle. This may lead to uncertainty the results. Additionally, the long-term follow-up may entail missing data, potentially introducing population selection bias into the database. Secondly, the definition NAFLD using FLI, based on biochemical markers rather than liver biopsy, may lead to misclassification and an insufficient sample size to exclude related causes, including iron overload, genetic factors, and autoimmune hepatitis, thereby affecting diagnostic accuracy. Concurrently, the fasting glucose and insulin tests, essential for the USFLI-based NAFLD diagnosis, were conducted in only a limited subset of participants. Consequently, this resulted in an insufficient sample size to robustly conduct a sensitivity analysis assessing the impact of OBS on NAFLD mortality. In addition, despite utilizing multiple regression analysis to adjust for some confounding factors, there may still be unaccounted variables influencing the accuracy of the results. Given the observational design of the study, establishing causality is challenging. Potential confounders and reverse causality could affect the interpretation of study conclusions. Lastly, considering that the NHAENS database is derived from a US cohort, the extrapolation of our findings to different races and countries warrants additional investigation in future research endeavors.

All in all, persisting with a diet and lifestyle rich in antioxidant can significantly reduce all-cause mortality and prevalence and mortality of CVD in the NAFLD population in the United States, offering potential benefits to individuals with both NAFLD and CVD. In this study, OBS played an important role, with both diet and life OBS demonstrating independent or combined protective effects against disease prevalence rate and mortality, especially among younger individuals and those with higher levels of education. We strongly advocate for the individualized management and treatment of NAFLD patients. Additionally, we recommend that future research adopts more rigorous experimental designs and utilizes comprehensive data sources for further validation and the expansion of these findings.

Publicly available datasets were analyzed in this study. This data can be found at: https://www.cdc.gov/nchs/nhanes/index.htm.

The studies involving humans were approved by the National Center for Health Statistics (NCHS) and Research Ethics Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

YinL: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Writing – original draft. YipL: Project administration, Supervision, Writing – review & editing.