Depression, a pervasive mental health disorder affecting over 350 million individuals globally, imposes profound physical, psychological, and socioeconomic burdens (Liu et al., 2023; Wang et al., 2023; Smith, 2014). The World Health Organization highlights its dual impact: diminished quality of life and elevated suicide risk, compounded by escalating prevalence linked to modern lifestyle stressors and demographic shifts (Sivertsen et al., 2015; Ruggieri, 2020). Alarmingly, adolescents face rising depression rates due to academic and social pressures, while older adults are vulnerable to age-related physiological decline and chronic comorbidities (Hu et al., 2022; Blazer, 2003; Shorey et al., 2022).

Emerging evidence underscores bidirectional links between cardiovascular and mental health (Barreto and Giatti, 2017; Lichtman et al., 2014; Whooley et al., 2008). Suboptimal cardiovascular metrics—hypertension, dyslipidemia, and obesity—may exacerbate depression via neuroinflammatory pathways, oxidative stress, and neurotransmitter dysregulation (Bica et al., 2017; Beurel et al., 2020; Wirtz and Von Känel, 2017). Conversely, depression-driven behavioral changes (e.g., sedentarism, poor diet) can potentiate cardiovascular dysfunction, creating a deleterious feedback loop (Carney et al., 2024).

In 2022, the American Heart Association introduced Life's Essential 8 (LE8), a multidimensional cardiovascular health framework expanding upon Life's Simple 7 by integrating sleep health (Lloyd-Jones et al., 2022a; Lloyd-Jones et al., 2022b). This composite metric evaluates eight modifiable domains: diet, physical activity, nicotine exposure, sleep, BMI, lipids, blood glucose, and blood pressure—each critically influencing neurophysiological processes (Chen et al., 2023; Li et al., 2023). For instance, balanced nutrition supports neurotransmitter synthesis, exercise enhances cerebral perfusion, and restorative sleep facilitates neural plasticity (Pearce et al., 2022; Swainson et al., 2023; Yasugaki et al., 2025; You et al., 2024a; You et al., 2024b).

Although cardiovascular-healthy lifestyles correlate with reduced depression risk (Shen and Zou, 2024; Zou et al., 2024; Zeng et al., 2024), LE8-specific relationships remain poorly characterized, accumulating evidence suggests sex differences in the relationship between cardiovascular health and depression, potentially due to a combination of biological factors (e.g., distinct hormonal and genetic influences) and sociobehavioral factors. Clarifying these associations could inform precision prevention strategies, leveraging LE8's actionable components to disrupt the depression-cardiovascular comorbidity cycle (Liu et al., 2024a; Fan et al., 2024; You et al., 2025a). Leveraging nationally representative NHANES data, this study investigates LE8-depression associations, sexual heterogeneity, and mediating mechanisms, aiming to advance targeted intervention frameworks.