Heart Failure: Lipid Metabolism Disorders Driving Cellular Senescence Through a Vicious Cycle, and Possible Intervention Strategies

Heart failure (HF) is major and growing global health challenge, with lipid metabolism dysregulation recognized as a significant contributing factor. This review focuses on the emerging concept of the "metabolism-senescence axis", which plays a central role in disease development progression. Excess lipid metabolites, especially ceramides and diacylglycerols, contribute to cardiomyocyte injury through multiple mechanisms, including mitochondria dysfunction, promoting oxidative stress, and interfering with normal metabolic signals. The senescence-associated secretory phenotype (SASP) promotes a pro-senescent tissue microenvironment, thereby disrupting the normal metabolic balance and creating a vicious cycle that seriously affects heart structure and function. This review examines the molecular events underlying this process, including cellular injury, impaired fatty acid oxidation, oxidative stress, activation of the p53/p21 and p16INK4a/Rb, signaling pathways, and SASP-mediated metabolic dysfunction. We further discuss the rationale for combinatorial strategies targeting both metabolic dysfunction and cellular senescence, proposing that simultaneous intervention in these interconnected pathways may represent a promising therapeutic approach to delay the progression of HF and improve patient outcomes.