Socioeconomic disadvantage and unhealthy lifestyles are both associated with greater physiological wear (allostatic load). Whether socioeconomic conditions modify the associations between health-related behaviors and allostatic load is unclear. We analyzed data from 24,187 US adults (National Health and Nutrition Examination Survey [NHANES] 2007–2018) and 17,507 Chinese adults (China Health and Retirement Longitudinal Study [CHARLS] 2011, extended follow-up to 2020). Socioeconomic disadvantage was quantified using country-specific Social Determinants of Health (SDoH) scores, and cumulative physiological wear was assessed via the Allostatic Load (AL) score. Following an exploratory XGBoost-based ranking of candidate predictors, survey-weighted generalized linear models and restricted cubic splines (RCS) were applied to evaluate socioeconomic effect modification on AL. Finally, survey-weighted Cox proportional hazards models were used to assess subsequent all-cause mortality risks. Clear but opposite socioeconomic gradients in allostatic load were observed: age- and sex-adjusted allostatic load declined with higher SDoH in the US (2.13 to 1.68; P for trend < 0.001) and increased in China (2.91 to 3.46; P for trend < 0.001). SDoH modified the association between systolic blood pressure and allostatic load in both cohorts (q = 0.030 in the US and q < 0.001 in China); the diastolic blood pressure interaction remained significant after FDR correction only in China (q = 0.010). This systolic interaction was attenuated after removing blood pressure components from the allostatic load score (US trend P = 0.006). In China, the association between allostatic load and current smoking was also modified by SDoH (P_interaction = 0.010; q = 0.033). In the US, body-mass index also showed an SDoH interaction that survived FDR correction (q = 0.030). No other factor retained significance in either cohort. In the US, the lowest SDoH stratum had substantially higher all-cause mortality than the highest (HR = 5.55; 95% CI 4.12–7.47), and allostatic load was independently associated with mortality (per 1-SD: HR = 1.37; 1.23–1.54). In China, both allostatic load (per 1-SD: HR = 1.18; 1.11–1.26) and socioeconomic disadvantage (lowest vs. highest SDoH stratum: HR = 1.78; 1.30–2.45) predicted all-cause mortality. The allostatic load–mortality association was consistent in the full sample and after excluding deaths within the first 12 months. Socioeconomic conditions were associated with variations in the associations between health-related behaviors and allostatic load, most consistently for blood pressure in both cohorts and for smoking in China, whereas the shape of the diet quality–allostatic load association did not differ significantly across socioeconomic strata. The divergent physiological patterns indicate that the relationship between social position and physiological dysregulation differs across populations. Strategies to promote equitable healthy aging must address both structural barriers and individual behaviors, though these observational findings warrant confirmation in prospective cohorts.

Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor, has garnered attention for its cardiovascular benefits beyond glycemic control. Ferroptosis, a novel form of regulated cell death, contributes to the pathogenesis of diabetic cardiomyopathy (DCM). However, whether EMPA mitigates DCM by suppressing ferroptosis remains unclear. Here, Type 2 diabetic db/db mice were used to establish a DCM model and treated with EMPA (10 mg/kg/day) for 12 weeks. EMPA significantly improved cardiac function, reduced myocardial fibrosis, and attenuated ferroptosis, concomitant with upregulated silent information regulator 3 (SIRT3) expression. In the rat cardiomyocytes (H9c2 cells) exposed to high glucose and palmitic acid, EMPA treatment or SIRT3 overexpression alleviated oxidative stress, mitochondrial dysfunction, and ferroptosis. Mechanistically, molecular docking, molecular dynamics simulation, cellular thermal shift assay and drug affinity responsive target stability assay confirmed that SIRT3 is the drug target of EMPA, stabilizing its protein levels and reducing acetylated p53 expression. Notably, SIRT3 silencing abolished EMPA’s beneficial effects on oxidative stress and ferroptosis. Our findings demonstrate that EMPA exerts cardioprotective effects by inhibiting oxidative stress and ferroptosis in cardiomyocytes, which is mediated by SIRT3. This study provides novel insights into the mechanisms underlying EMPA’s therapeutic effects in DCM.