Obesity leads to numerous illnesses and metabolic disorders, with lysophosphatidylcholine (LPC) levels declining in obese patients. However, the physiological role of LPC and the regulatory mechanisms involved in modulating obesity remain largely unknown. Here, we provide evidence that 1-linoleoylglycerophosphocholine (1-LGPC) promotes adipocyte energy expenditure by activating the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) axis. Metabolomic analyses identified 1-LGPC as a characteristic metabolite that declined in the peripheral blood of obese patients. Treatment with 1-LGPC effectively alleviated high-fat diet-induced lipid accumulation in zebrafish larvae and human adipocytes. Elevated expression levels, increased oxygen consumption rates, and enhanced transcript levels indicated that uncoupling protein 1-dependent thermogenesis and mitochondrial respiration were significantly boosted. Furthermore, NRF2 expression and nuclear translocation were induced by 1-LGPC, and NRF2 inhibition triggered UCP1 downregulation and lipid accumulation restoration, confirming the KEAP1-NRF2 axis's involvement in 1-LGPC-induced energy expenditure. These findings offer preliminary insights into physiological roles and mechanisms by which 1-LGPC modulates lipid and energy metabolism, providing potential strategies for obesity intervention using clinically identified compounds.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.