Targeting ACSL1 Attenuates HKMT-Induced Metabolic Reprogramming and Inflammation in Macrophages During Mycobacterium tuberculosis Infection 2060

Abstract Description Mycobacterium tuberculosis (MTB) evades immune clearance by reprogramming macrophage metabolism to favor glycolysis over oxidative phosphorylation, known as the Warburg effect. This metabolic shift not only supports bacterial survival, but it drives a pro-inflammatory state. Acyl-CoA synthetase long-chain family member 1 (ACSL1) is a key lipid-metabolizing enzyme implicated in regulating immune cell metabolism and inflammation. This study explores ACSL1’s role in mediating these immuno-metabolic alterations in macrophages during MTB infection and its potential as a therapeutic target. THP-1-derived macrophages were exposed to heat-killed M. tuberculosis (HKMT), and ACSL1 expression was assessed. Triacsin C (TRI) was used to inhibit ACSL1, and downstream effects on inflammatory markers, and metabolic reprogramming were evaluated using molecular assays and metabolic profiling. HKMT significantly upregulated ACSL1 and induced a Warburg-like effect, by increased glycolytic markers and reduced fatty acid oxidation. TRI reversed these metabolic shifts, restoring oxidative metabolism and reducing pro-inflammatory cytokine production.Its inhibition also normalized glucose uptake, ATP content, and mitochondrial function in HKMT-treated macrophages. ACSL1 plays a pivotal role in MTB-induced metabolic-reprogramming and inflammatory responses. Targeting ACSL1 may represent a novel therapeutic strategy to enhance macrophage function and improve host defenses against tuberculosis. Funding Sources This work was supported by Kuwait Foundation for the Advancement of Sciences Grant RA CB-2023-017 (FAR.) Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)