Abstract: Acyl-CoA synthetase short-chain family member 1 (ACSS1) is a key metabolic enzyme located in the mitochondrial matrix. The primary function is to catalyze the synthesis of acetyl-CoA from acetate and coenzyme A, which then enters the tricarboxylic acid (TCA) cycle and undergoes oxidative breakdown to produce ATP, providing energy for the body. It plays a central role in cellular energy homeostasis, lipid synthesis, and epigenetic regulation. ACSS1 has a clear gene localization and tissue-specific expression pattern, and the protein structure is conserved. Under glucose deprivation or stress conditions, ACSS1 can use alternative carbon sources such as acetate to synthesize acetyl-CoA, providing substrates for the TCA cycle and maintaining ATP production, thereby ensuring energy stability in high-energy-demand tissues such as the heart and brain. The molecular structure of ACSS1 contains a conserved lysine acetylation site (mouse K635/human K642), which is dynamically regulated by the deacetylase silent information regulator transcript 3 (SIRT3). Especially under conditions of nutrient deprivation (such as fasting) or oxidative stress, SIRT3 activates ACSS1 enzymatic activity through deacetylation, promoting the utilization of acetate to maintain energy balance. Under normal physiological conditions, ACSS1 is involved in maintaining energy during fasting, hepatic ketogenesis, and cardiac ATP supply. In pathological conditions, ACSS1 dysfunction is associated with various diseases: it supports cancer cell survival under low nutrient conditions in tumors; its decline may lead to energy depletion in neurodegenerative diseases; in addition, it is closely related to metabolic diseases such as fatty liver and sarcopenia. Through a systematic reviewed of existing studies, this review aimed to provide a theoretical basis for understanding the regulatory pathways and molecular mechanisms of ACSS1 in energy metabolism.

Key words: pig, ACSS1, energy metabolism, Acetyl-CoA, epigenetic regulation, lipid synthesis, cellular energy homeostasis, ATP