Abstract Body: Atherosclerosis, a chronic inflammatory disease fueled by cholesterol deposition in artery walls, remains the leading cause of death worldwide. Resolution of atherosclerotic inflammation and plaque regression are important clinical goals. Long noncoding RNAs (lncRNAs) have emerged as powerful regulators of gene expression, sparking intense interest in their roles and therapeutic potential in atherosclerosis. To uncover lncRNAs driving plaque development, we conducted single-cell RNA sequencing on CD45⁺ immune cells infiltrating aortic arch plaques of Ldlr^–/– mice during plaque progression (16 weeks Western diet; WD) or regression (16 weeks WD + 4 weeks apoB ASO). This approach revealed a novel lncRNA that we named Caslr (Ctsc antisense lncRNA). Caslr is transcribed from the opposite strand of the Cathepsin C gene (Ctsc) which encodes a pro-atherosclerotic lysosomal protease. The Caslr–Ctsc pair is upregulated in macrophages of progressing plaques and in response to pro-inflammatory stimuli (i.e., LPS, IL-6) in vitro, while it is conversely downregulated during atherosclerosis regression and under anti-inflammatory stimulation (i.e., IL-4). LncRNA knockdown approaches combined with transcriptomic analyses and functional assays revealed that Caslr controls Ctsc expression, impacting key inflammatory pathways such as NF-kB signaling and NLRP3 inflammasome activation, ASC speck formation and IL-1β release. Importantly, mice with hematopoietic deficiency of Caslr show reduced atherosclerosis plaque burden and complexity along with decreased ASC speck and IL-1β levels, indicating an important role for Caslr in driving atherosclerotic inflammation via NLRP3 inflammasome activation. Using RNA purification strategies combined with mass-spectrometry, we show that Caslr interacts with spliceosome-associated proteins to coordinate Ctsc mRNA splicing, and identify the human syntenic lncRNA CASLR that shares functional homology in governing CTSC expression and NLRP3 inflammasome activation. Notably, human CASLR and CTSC are highly expressed in the blood of hyperlipidemic patients and their expression is coordinately decreased after aggressive cholesterol-lowering treatment. Collectively, our data identify Caslr as an evolutionarily conserved cis-acting lncRNA that orchestrates major inflammatory pathways in plaque macrophages, and suggest that targeting lncRNAs impeding resolution of inflammation could unlock new strategies for atherosclerosis treatment.