Decoding the crosstalk: interplay between macrophage programmed cell death networks and cholesterol efflux.

Atherosclerosis is driven by the interplay between lipid accumulation, chronic inflammation, and macrophage dysfunction. Although intensive lipid-lowering therapy reduces cardiovascular risk, substantial residual risk persists, highlighting the importance of impaired macrophage cholesterol handling and reverse cholesterol transport (RCT). This review summarizes the bidirectional relationships between macrophage programmed cell death and cholesterol metabolism, with a focus on apoptosis, pyroptosis, necroptosis, and ferroptosis, which have been comparatively well studied in atherosclerosis and have direct or indirect links to macrophage cholesterol handling. Apoptosis may support plaque homeostasis when apoptotic cells are efficiently cleared by efferocytosis, thereby limiting inflammation and promoting LXR-dependent cholesterol efflux. In contrast, defective efferocytosis can lead to secondary necrosis and inflammatory amplification. Pyroptosis, necroptosis, and ferroptosis may impair macrophage cholesterol homeostasis through overlapping mechanisms involving inflammatory signaling, oxidative stress, membrane disruption, reduced ABCA1/ABCG1-dependent efflux, and HDL dysfunction. Autophagy and lipophagy exert context-dependent effects: appropriate autophagic flux facilitates intracellular cholesterol mobilization, whereas excessive or dysregulated autophagy may increase ferroptotic susceptibility through ferritinophagy, iron release, and GPX4 loss. Based on these observations, we propose a macrophage death-mode bifurcation framework centered on caspase-8 activity, RIPK1 ubiquitination, mitochondrial stress, oxidative stress thresholds, and autophagic flux. These interconnected nodes may influence whether macrophages undergo apoptosis with efficient clearance or inflammatory and lytic death associated with impaired net cholesterol flux. However, the strength of evidence differs among death modalities, and many proposed links remain indirect or primarily supported by preclinical studies. This framework provides a basis for future studies integrating cell-death regulation, cholesterol transport, and plaque stability.