【摘要】 目的：抑郁症是一种复杂的精神障碍，其所致的疾病负担已成为全球重大公共卫生问题。性别是抑郁易感性的重要影响因素，然而其具体机制尚未明确。研究表明，抑郁症与酰基肉碱代谢存在显著关联，但目前针对不同性别抑郁症患者酰基肉碱代谢谱的系统比较仍较缺乏。本研究旨在探讨首发、未用药抑郁症患者血浆酰基肉碱代谢特征的性别差异，分析不同性别群体中特定酰基肉碱与抑郁易感性及严重程度的关系，从代谢组学视角揭示抑郁症性别差异的潜在生物学机制。方法：基于2017至2020年开展的临床试验收集的首发未用药抑郁症患者和健康对照的血浆样本进行肉碱测定，共纳入100名首发、未用药抑郁症患者和50名健康对照。采用基于超高效液相色谱-四极杆飞行时间质谱定性鉴定与液相色谱-串联质谱靶向定量检测相结合的2步分析策略，对血浆酰基肉碱代谢谱进行系统检测。通过双因素方差分析或Scheirer-Ray-Hare检验探究抑郁诊断和性别差异对酰基肉碱水平的影响，并进一步通过多元线性回归分析明确酰基肉碱与性别、抑郁风险及严重程度的关联。结果：血浆中共检出33种酰基肉碱及游离肉碱，通过初步分析与筛选，其中8种酰基肉碱存在显著的性别差异。针对具有显著性别差异的酰基肉碱指标进行进一步分析，将患者基线特征纳入多元线性回归模型后发现：乙酰肉碱C2:0(β=0.910,P=0.023)、戊酰肉碱C5:0(β=-0.020,P=0.012)、十一碳烯酰肉碱C11:1(β=-3.322,P=0.008)水平与性别存在显著相关性。将患者基线特征及具有性别差异的肉碱指标纳入自变量，以多种量表得分作为因变量构建多元线性回归模型，结果表明：C11:1与贝克抑郁自评量表(Beck Depression Inventory,BDI)得分呈显著正相关(β=0.817,P=0.036),C12:1-OH(β=0.774,P=0.034)与汉密尔顿焦虑量表(Hamilton Anxiety Scale,HAMA)得分呈显著正相关，C4:0(β=-44.616,P=0.028)和C13:1(β=-1.344,P=0.022)与HAMA得分呈显著负相关。结论：首发抑郁症患者的酰基肉碱代谢存在显著性别差异，其中C2:0、C5:0和C11:1为受性别独立调控的关键代谢物，C4:0、C11:1、C12:1-OH和C13:1与抑郁易感性及焦虑严重度密切相关，提示线粒体脂肪酸氧化代谢通路功能失调可能是抑郁症性别差异的重要生物学基础，为抑郁症精准分型及性别特异性诊疗策略开发提供了新方向。更多还原

【Abstract】 Objective: Depression is a complex mental disorder whose disease burden has become a major global public health issue. Sex is an important factor influencing susceptibility to depression, but the underlying mechanisms remain unclear. Previous studies have demonstrated a significant association between depression and acylcarnitine metabolism; however, systematic comparisons of acylcarnitine metabolic profiles between male and female patients with depression remain limited. This study aims to investigate sex differences in plasma acylcarnitine metabolic characteristics in first-episode, drug-na??ve patients with depression, analyze the relationships between specific acylcarnitines and depression susceptibility and severity in different sexes, and explore the potential biological mechanisms underlying sex differences in depression from a metabolomics perspective.Methods: Plasma samples from first-episode, drug-na??ve patients with depression and healthy controls collected in a clinical trial conducted between 2017 and 2020 were analyzed for carnitine levels. A total of 100 patients with first-episode, drug-na??ve depression and 50 healthy controls were included. A two-step analytical strategy combining qualitative identification using ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF MS) and targeted quantification using liquid chromatography-tandem mass spectrometry(LC-MS/MS) was applied to systematically detect plasma acylcarnitine metabolic profiles. Two-way analysis of variance(ANOVA) or the Scheirer-Ray-Hare test was used to examine the effects of depression diagnosis and sex differences on acylcarnitine levels. Multivariate linear regression analysis was further conducted to determine the associations between acylcarnitines, sex, depression susceptibility, and severity.Results: A total of 33 acylcarnitines and free carnitine were detected in plasma. After preliminary analysis and screening, 8 acylcarnitines showed significant sex differences. Further multivariate linear regression analysis incorporating baseline characteristics revealed that acetylcarnitine C2:0(β=0.910, P=0.023), valerylcarnitine C5:0(β=-0.020, P=0.012), and undecylenoylcarnitine C11: 1( β =-3.322, P=0.008) were significantly associated with sex. When baseline characteristics and sex-differentiated acylcarnitines were included as independent variables and scale scores were used as dependent variables in multivariate linear regression models, C11: 1 showed a significant positive correlation with Beck Depression Inventory(BDI) scores(β=0.817, P=0.036). C12:1-OH(β=0.774, P=0.034) was positively correlated with Hamilton Anxiety Scale(HAMA) scores, whereas C4:0(β =-44.616, P=0.028) and C13: 1(β =-1.344, P=0.022) were negatively correlated with HAMA scores(P<0.05).Conclusion: This study demonstrated significant sex differences in acylcarnitine metabolism in patients with first-episode depression. Among them, C2:0, C5:0, and C11:1 were key metabolites independently regulated by sex. C4:0, C11:1, C12:1-OH, and C13:1 were closely associated with depression susceptibility and anxiety severity. These findings suggest that dysregulation of mitochondrial fatty acid β-oxidation pathways may represent an important biological basis for sex differences in depression and provide new directions for precision classification and sex-specific diagnostic and therapeutic strategies for depression.更多还原