Atherosclerotic cardio-cerebrovascular diseases remain the leading contributor to global disease burden and mortality. Impaired efferocytosis—the clearance of apoptotic cells by macrophages—is known to exacerbate inflammation and promote necrotic core formation within atherosclerotic plaques. Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis development. However, the role of long non-coding RNAs (lncRNAs) induced by Hcy in this process remains largely unexplored. Here, we demonstrate that Hcy impairs macrophage efferocytosis and enhances inflammation in atherosclerosis, both in HMD-fed ApoE-/- mice and in RAW264.7 cells treated with Hcy. We further identify a markedly up-regulated lncRNA in Hcy-induced macrophages, termed macrophage efferocytosis-related lncRNA (MAERL). Knockdown of MAERL attenuated the impairment of efferocytosis and reduced inflammation. Mechanistically, MAERL interacts with and inhibits TGM2, thereby significantly suppressing macrophage efferocytosis and promoting inflammation. Collectively, these findings reveal a MAERL/TGM2 pathway in macrophages as a key regulatory mechanism in the development of atherosclerosis.
Xiao et al. (2026) studied this question.