Hsu Chien-Ning, Chen Chih-Kuang, Hou Chih-Yao, Chen Yu-Wei, Chang-Chien Guo-Ping, Lin Shu-Fen, Tain You-Lin
Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
Department of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan.
Antioxidants (Basel). 2025 Sep 19;14(9):1136. doi: 10.3390/antiox14091136.
Cardiovascular-kidney-metabolic syndrome (CKMS) encompasses interconnected cardiovascular, renal, and metabolic disorders, including obesity, hypertension, and type 2 diabetes. Oxidative stress is increasingly recognized as a central driver of this multi-organ dysfunction. Among maternal influences, exposure to a high-fat diet (HFD) during pregnancy and lactation consistently predisposes offspring to CKMS-related phenotypes in animal models. While oxidative stress is implicated as a key mediator, its precise role in developmental programming remains unclear, and comparing the differences in its role between overt CKMS and CKM programming is critical. Critical gaps include whether oxidative stress acts uniformly or in an organ- and time-specific manner, which signals initiate long-term redox alterations, and whether these effects are reversible. Furthermore, its interactions with other programming pathways-such as renin-angiotensin system activation, epigenetic dysregulation, gut microbiota imbalance, and altered nutrient sensing-remain insufficiently explored. This review uniquely highlights maternal HFD-induced oxidative stress as a mechanistic axis of CKMS programming and delineates unresolved questions that limit translation. By integrating evidence across organ systems and proposing priorities for multi-organ profiling, refined models, and longitudinal human studies, we outline a forward-looking agenda for the field. Ultimately, clarifying how maternal HFD and oxidative stress shape offspring CKMS risk is essential to inform targeted antioxidant strategies to reduce the intergenerational transmission of CKMS risk.
心血管-肾脏-代谢综合征（CKMS）包括相互关联的心血管、肾脏和代谢紊乱，如肥胖、高血压和2型糖尿病。氧化应激日益被认为是这种多器官功能障碍的核心驱动因素。在母体影响因素中，孕期和哺乳期暴露于高脂饮食（HFD）会使动物模型中的后代持续易患与CKMS相关的表型。虽然氧化应激被认为是关键介质，但其在发育编程中的精确作用仍不清楚，比较其在显性CKMS和CKM编程中的作用差异至关重要。关键差距包括氧化应激是均匀起作用还是以器官和时间特异性方式起作用，哪些信号引发长期氧化还原改变，以及这些影响是否可逆。此外，其与其他编程途径（如肾素-血管紧张素系统激活、表观遗传失调、肠道微生物群失衡和营养感知改变）的相互作用仍未得到充分探索。本综述独特地强调了母体高脂饮食诱导的氧化应激作为CKMS编程的机制轴，并阐述了限制转化的未解决问题。通过整合各器官系统的证据并提出多器官分析、完善模型和纵向人体研究的优先事项，我们为该领域勾勒了一个前瞻性议程。最终，阐明母体高脂饮食和氧化应激如何塑造后代CKMS风险对于制定有针对性的抗氧化策略以减少CKMS风险的代际传递至关重要。
