此前瞻性研究旨在探讨未接受降脂治疗的人群中，基线胆固醇水平及其纵向变化，尤其是低水平，与全因和特定原因死亡风险在不同人群之间的关联。研究对象来自两项中国队列和英国生物银行（UK Biobank，UKB）。为尽量减少反向因果推断，排除了基线时使用降脂药物，患有冠心病、脑卒中、癌症、临床诊断的慢性阻塞性肺疾病、或体质指数<18.5 kg/m^²，以及随访前两年内死亡的研究对象。此外，对参加超过四年后重复调查的个体评估胆固醇变化情况。通过登记系统关联获取死亡数据，并采用Cox比例风险模型评估死亡风险。研究共纳入163 115名中国成年人和317 305名UKB成年人（平均年龄49~61岁）。其中，东风-同济队列、开滦研究和UKB队列的男性比例分别为43%、81%和44%。在中位随访9.7~12.9年期间，中国队列和UKB分别记录了9553和15 760例死亡。多变量调整后，观察到总胆固醇（total cholesterol，TC）、低密度脂蛋白胆固醇（low-density lipoprotein cholesterol，LDL-C）和非高密度脂蛋白胆固醇（non-high-density lipoprotein cholesterol，non-HDL-C）与死亡风险呈非线性关系。在中英人群中均观察到，高胆固醇水平主要与冠心病死亡相关，而低胆固醇水平则与全因和癌症死亡相关（P_nonlinear ≤ 0.0161）。中国队列人群在TC、LDL-C和non-HDL-C的范围分别是160~200 mg∙dL^⁻¹、100~130 mg∙dL^⁻¹和130~160 mg∙dL^⁻¹时全因死亡风险最低，低于UKB人群，是对应血脂的最佳范围。此外，在中国队列中，四年间胆固醇水平动态下降与全因和癌症死亡风险升高显著关联（P_nonlinear ≤ 0.0100）。基线和重复调查均表现为低TC、LDL-C或non-HDL-C水平的中英人群、以及基线低或中等水平且动态下降超过20%的中国人群，均经历了更高的全因死亡风险。综上，高水平的TC、LDL-C和non-HDL-C与冠心病死亡风险升高有关。重要的是，基线低及动态下降的胆固醇水平与全因和癌症死亡风险升高存在稳健的关联，可能作为过早死亡的潜在标志。建议定期监测胆固醇水平，在关注高水平的同时也需警惕低水平，以指导指南更新和临床策略。

This prospective study aimed to investigate the associations of untreated cholesterol levels and their longitudinal changes, especially low levels, with all-cause and cause-specific mortality in different populations. Participants were drawn from two Chinese cohorts and the UK Biobank, excluding those with lipid-lowering medications, coronary heart disease (CHD), stroke, cancer, clinically diagnosed chronic obstructive pulmonary disease, low body mass index (< 18.5 kg∙m^–2) at baseline, and deaths within the first two years to minimize reverse causality. Individual cholesterol changes were assessed in a subset who attended the resurvey after over four years. Mortality data were linked to registries, and risks were estimated using Cox proportional hazards models. A total of 163 115 Chinese and 317 305 UK adults were included (mean age, 49–61 years), with 43%, 81%, and 44% males in Dongfeng–Tongji, Kailuan, and UK Biobank cohorts, respectively. During a median follow-up of 9.7–12.9 years, 9553 and 15 760 deaths were documented in the Chinese cohorts and UK Biobank, respectively. After multivariate adjustments, nonlinear relationships were observed between total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) levels and mortality. In both populations, high cholesterol was primarily associated with CHD mortality, while low cholesterol associated with all-cause and cancer mortality (P_nonlinear ≤ 0.0161). The optimal levels for all-cause mortality risk in Chinese adults (TC: 200 mg∙dL^–1; LDL-C: 130 mg∙dL^–1; non-HDL-C: 155 mg∙dL^–1) were lower than those in the UK Biobank but consistent with guideline recommendation. Additionally, decreasing cholesterol levels over four years were associated with higher all-cause and cancer mortality in the Chinese cohorts (P_nonlinear ≤ 0.0100). Participants with low TC, LDL-C, or non-HDL-C levels at both baseline and resurvey experienced elevated all-cause mortality risks in both populations, as did those with low/medium baseline levels and > 20% reductions over time in Chinese adults. In conclusion, higher TC, LDL-C, and non-HDL-C levels are associated with elevated CHD mortality. Importantly, low and/or longitudinally decreasing cholesterol levels are robustly associated with increased all-cause and cancer mortality, potentially serving as markers of premature death. Regular cholesterol monitoring, with attention to both high and low levels, is recommended to inform guideline updates and clinical strategies.