ATF2-LPCAT1-mediated PKM2 acetylation links cholesterol stress to macrophage metabolic reprogramming and functional remodeling

Pyruvate kinase M2 (PKM2) regulates cellular metabolism under stress. However, mechanisms involving PKM2 modification in cholesterol-loaded macrophages remain unclear. In this study, we first characterized the impact of cholesterol loading on macrophage functional and metabolic alterations. Although cholesterol loading did not alter PKM2 expression, it regulated PKM2 function by promoting its acetylation. Specifically, PKM2 acetylation at lysine 433 (K433) exacerbated cholesterol-induced metabolic disorders and inflammation, whereas K433 mutations ameliorated these effects. Mechanistically, cholesterol activated the p38 mitogen-activated protein kinase (MAPK) pathway, inducing activating transcription factor 2 (ATF2) and upregulating lysophosphatidylcholine acyltransferase 1 (LPCAT1) to promote PKM2 acetylation. Collectively, PKM2 acetylation mediates cholesterol-induced metabolic and functional reprogramming in macrophages, highlighting the novel p38-ATF2-LPCAT1-PKM2 axis in immune stress signaling.