Efficient fatty acid (FA) re-esterification is essential for lipid homeostasis in adipocytes, yet the mechanisms coordinating Coenzyme A (CoA) availability at the endoplasmic reticulum (ER)-a major site of lipid synthesis-remain unclear. Here, we identify TMEM120A as an ER-resident CoA-binding protein that regulates intracellular FA metabolism. TMEM120A interacts with the ER-localized acyl-CoA synthetase ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and channeling into the ER, thereby facilitating FA re-esterification and lipid cycling during lipolysis. By relieving acyl-CoA-mediated feedback inhibition of lipolysis, TMEM120A enhances lipid turnover while protecting against ER stress and lipotoxicity. Adipocyte-specific deletion of Tmem120a in mice impairs lipolysis-induced energy expenditure and exacerbates inflammation and metabolic dysfunction under high-fat diet conditions. These findings establish TMEM120A as a critical regulator of ER CoA handling and lipid flux, revealing a previously unrecognized mechanism that links intracellular CoA dynamics to systemic energy balance and metabolic health.
© 2025. The Author(s).