ACSL1

ACSL1 Full Name

acyl-CoA synthetase long-chain family member 1

ACSL1 Introduction

Acyl-CoA synthetase long-chain family member 1 (ACSL1) is a critical metabolic enzyme that serves as a fundamental gatekeeper in cellular lipid metabolism. Localized primarily to the outer mitochondrial membrane and the endoplasmic reticulum, ACSL1 catalyzes the essential first step of fatty acid utilization. Its primary physiological function is to convert free long-chain fatty acids (LCFAs, typically containing 12 to 20 carbon atoms) into their active fatty acyl-CoA thioesters. This ATP-dependent activation is an absolute prerequisite; without it, LCFAs cannot enter any downstream metabolic pathways. Because it channels activated lipids primarily toward mitochondrial beta-oxidation, ACSL1 is abundantly expressed in tissues with high energy demands, such as the heart, liver, skeletal muscle, and brown adipose tissue. By dictating the intracellular fate of fatty acids, ACSL1 plays an indispensable role in maintaining systemic energy homeostasis and preventing ectopic lipid accumulation.

Figure 1. Regulatory mechanisms of the long-chain acyl-CoA synthetase (ACSL) family members in different cancers. (Source: Zhang L, et al. 2023)

Given its central role in energy dynamics, the dysregulation of ACSL1 is heavily implicated in a broad spectrum of metabolic and cardiovascular diseases. In the context of metabolic syndrome, impaired ACSL1 function or abnormal lipid channeling can lead to severe lipotoxicity, exacerbating insulin resistance and driving the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). In the cardiovascular system, optimal ACSL1 activity is vital for cardiac contractility; its deficiency disrupts cardiac ATP production, ultimately leading to hypertrophic cardiomyopathy and heart failure.

Beyond metabolic disorders, ACSL1 has recently emerged as a highly significant player in oncology and programmed cell death, particularly ferroptosis. Cancer cells frequently upregulate ACSL1 to fuel their rapid proliferation through enhanced beta-oxidation. However, this enzyme also presents a unique vulnerability. By activating specific polyunsaturated fatty acids (PUFAs), ACSL1 incorporates them into cellular membranes, which can paradoxically sensitize highly aggressive tumor cells to lipid peroxidation and ferroptosis. Consequently, ACSL1 acts as a metabolic double-edged sword: it promotes tumor energy production but also regulates susceptibility to ferroptotic cell death. This complex, context-dependent dual role makes ACSL1 an intensely studied prognostic biomarker and a promising therapeutic target for treating both severe metabolic dysfunctions and chemoresistant cancers.

Alternate Names for ACSL1

ACSL1; acyl-CoA synthetase long-chain family member 1; ACS1; LACS; FACL1; FACL2; LACS1; LACS2; long-chain-fatty-acid--CoA ligase 1; LACS 1

• 1. Ma Y, et al. Long-chain fatty acyl-CoA synthetase 1 promotes prostate cancer progression by elevation of lipogenesis and fatty acid beta-oxidation. Oncogene. 2021 Mar;40(10):1806-1820.
  2. Zhang L, et al. Characteristics of long-chain acyl-CoA synthetases in metabolism and cancer. Clin Transl Disc. 2023;3:e200.