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Background: Stressful life events (SLEs) are well-established proximal predictors of the onset of depression. However, the fundamental causes of interindividual differences in depression outcomes are poorly understood. This study addressed this depression susceptibility mechanism using a well-powered sample of adults living in China.Methods: Healthy participants with SLEs (n = 185; mean = 47.51 years, 49.73% female), drawn from a longitudinal study on the development of depression, underwent diffusion tensor imaging, interleukin-6 (IL-6) level measurement, and trimonthly standardized clinical and scale evaluations within a two-year period.Results: Receiver operating characteristic analyses indicated that reduced feeder connection and HIP.R nodal efficiency improved the predictive accuracy of post-SLEs depression (ORfeeder = 0.623, AUC = 0.869, P < 0.001; ORHIP = 0.459, AUC = 0.855, P < 0.001). The successfully established path analysis model confirmed the significant partial effect of SLEs-IL-6-white matter (WM) network differences-depression (onset and severity) (x2/8 = 1.453, goodness-of-fit [GFI] = 0.935, standard root-mean-square error of approximation [SRMR] = 0.024). Females, individuals with lower exercise frequency (EF) or annual household income (AHI) were more likely to have higher IL-6 level after SLEs (βint-female⁎SLEs = -0.420, P < 0.001; βint-exercise⁎SLEs = -0.412, P < 0.001; βint-income⁎SLEs = -0.302, P = 0.005).Limitations: The sample size was restricted due to the limited incidence rate and prospective follow-up design.Conclusions: Our results suggested that among healthy adults after SLEs, those who exhibited abnormal IL-6-WM differences were susceptible to developing depression. Females, lower AHI or EF might account for an increased risk of developing these abnormal IL-6-WM differences. [ABSTRACT FROM AUTHOR]