MAERL accelerates atherosclerosis by inhibiting macrophage efferocytosis via transglutaminase 2

Atherosclerotic cardiovascular and cerebrovascular diseases continue to represent the leading cause of global disease burden and mortality. Defective efferocytosis the phagocytic clearance of apoptotic cells by macrophages, is a well-established pathological mechanism that fuels chronic inflammation and drives necrotic core expansion in atherosclerotic plaques. Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis development. However, the role of long non-coding RNAs (lncRNAs) induced by homocysteine (Hcy) in this process remains largely unexplored. Here, we demonstrate that Hcy impairs macrophage efferocytosis and enhances inflammation in atherosclerosis, both in high methionine diet (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 attenuates the impairment of efferocytosis and reduces inflammation. Mechanistically, MAERL interacts with and inhibits transglutaminase 2 (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.