The ACSL4 Network Regulates Cell Death and Autophagy in Diseases

Abstract

Lipid metabolism, cell death, and autophagy are interconnected processes in cells. Dysregulation of lipid metabolism can lead to cell death, such as via ferroptosis and apoptosis, while lipids also play a crucial role in the regulation of autophagosome formation. An increased autophagic response not only promotes cell survival but also causes cell death depending on the context, especially when selectively degrading antioxidant proteins or organelles that promote ferroptosis. ACSL4 is an enzyme that catalyzes the formation of long-chain acyl-CoA molecules, which are important intermediates in the biosynthesis of various types of lipids. ACSL4 is found in many tissues and is particularly abundant in the brain, liver, and adipose tissue. Dysregulation of ACSL4 is linked to a variety of diseases, including cancer, neurodegenerative disorders, cardiovascular disease, acute kidney injury, and metabolic disorders (such as obesity and non-alcoholic fatty liver disease). In this review, we introduce the structure, function, and regulation of ACSL4; discuss its role in apoptosis, ferroptosis, and autophagy; summarize its pathological function; and explore the potential implications of targeting ACSL4 in the treatment of various diseases.

Regulation mechanisms of disulfidptosis-related genes in ankylosing spondylitis and inflammatory bowel disease

“…The long-chain acyl-CoA synthetase family (ACSL), located on the outer mitochondrial membrane and endoplasmic reticulum, catalyzes the conversion of fatty acids to acyl-CoA. Serving as intermediates in the lipid metabolic pathway, acyl-CoAs participate in various biological processes, including the maintenance of cell membrane structure, energy metabolism, and lipid metabolism (31). Among the key subtypes, ACSL1 and ACSL4 have been identified as crucial players.…”

“…Among the key subtypes, ACSL1 and ACSL4 have been identified as crucial players. ACSL1 was recently found to be a promoter of iron accumulation, while ACSL4 was considered instrumental in integrating polyunsaturated fatty acids (PUFA) into phospholipids, a significant event in iron accumulation (31,32). Iron accumulation was a form of non-apoptotic cell death driven by lipid peroxidation, with lipid metabolism being a major metabolic change during the process.…”

“…This inflammatory state might potentially result in local iron accumulation, initiating oxidative stress and activating the iron accumulation pathway (33). Although the specific mechanisms by which ACSL1 and ACSL4 participate in and regulate iron accumulation have not been fully understood, several studies suggested that they may serve as therapeutic targets for inhibiting iron accumulation (31,32). While the relationships of these genes with disulfidptosis have not been extensively studied, the aforementioned researches have suggested their potential associations with other cell death pathways.…”

Alkaliptosis induction counteracts paclitaxel‐resistant ovarian cancer cells via ATP6V0D1‐mediated ABCB1 inhibition

“…60,61 Consequently, there is a clinical need to foster more targeted and efficient forms of regulated cell death to combat cancer effectively. [62][63][64] The reversal of pH gradients and metabolic reprogramming are identified as hallmark characteristics of cancer cells. 65,66 The inversion of pH gradients also represents an initial event in tumorigenesis, contributing to subsequent cancer hallmarks, such as enhanced glycolytic activity and increased resistance to cell death.…”

Metabolic dysfunction-associated steatotic liver disease: ferroptosis related mechanisms and potential drugs

“…Based on these findings, it could be inferred that GPX4 may play a role in the inhibition of lipid peroxidation, the prevention of adipose tissue inflammation, as well as the mitigation of low-level systemic inflammation. In addition, ACSL4 may have effects such as promoting the participation of arachidonic acid in phospholipids, causing liver fat accumulation, and triggering inflammation of white adipose tissue (Chen et al, 2023). For example, specific knockout of ACSL4 in mouse adipocytes effectively prevented obesity induced by a high-fat diet and reduced levels of lipid peroxidation product 4-HNE (Killion et al, 2018).…”