Macrophage senescence and programmed cell death in atherosclerosis: Mechanisms, cross-talk, and emerging therapeutic strategies

Atherosclerosis imposes a heavy burden on global healthcare systems and remains the leading cause of mortality worldwide, with macrophage dysfunction playing a critical role in its pathogenesis. This review examines the dual roles of macrophage senescence and programmed cell death (PCD) in the progression of atherosclerosis, highlighting their mechanisms, cross-talk and emerging therapeutic strategies. Macrophage senescence-characterized by irreversible cell cycle arrest, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP)-exacerbates chronic inflammation and impairs tissue repair. Meanwhile, PCD pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy, regulate inflammatory responses and cellular homeostasis; however, their dysregulation accelerates arterial pathology. Shared molecular pathways such as NF-κB, mTOR, and p53 govern both processes, while distinct features define their respective contributions: senescence reflects cumulative damage and functional decline, whereas PCD involves regulated, context-dependent cellular demise. In atherosclerosis, senescent macrophages promote plaque instability through SASP-driven inflammation and impaired efferocytosis, while PCD modalities such as necroptosis and pyroptosis exacerbate necrotic core formation. Emerging therapeutic strategies targeting these pathways-including senolytics, NLRP3 inhibitors, ferroptosis suppressors, and autophagy enhancers-show promise in preclinical models by mitigating inflammation, restoring macrophage function, and stabilizing plaques. Pharmacological interventions such as quercetin (a p38 MAPK inhibitor), melatonin (an Nrf2 activator), and senolytic agents illustrate the potential to disrupt the senescence-PCD axis. This synthesis underscores the importance of delineating context-specific roles of macrophage senescence and PCD in atherosclerosis, offering a roadmap for dual-targeted therapies to alleviate cardiovascular burden. By integrating mechanistic insights with translational applications, this review identifies novel biomarkers and therapeutic avenues to combat aging-related atherosclerotic pathologies.