Lipid Metabolism/Ferroptosis Antibody Sampler Kit #58434

Mammalian long-chain acyl-CoA synthetase (ACSL) catalyzes the ligation of the fatty acid to CoA to form fatty acyl-CoA in a two-step reaction. Five isoforms of ACSL have been identified (1). Overexpression of ACSL1 results in changes to fatty acid metabolism in rat primary hepatocytes (2).

Studies show that exogenous monounsaturated fatty acids inhibit ferroptosis and that this process requires the activation of monounsaturated fatty acids by acyl-CoA synthetase long-chain family member 3 (ACSL3) (3). In addition, studies on a mouse model show that Acsl3 is essential for oleic acid to protect melanoma cells from ferroptosis, which leads to more tumor metastases (4). Furthermore, ACSL3 is required for prostaglandin synthesis and tumorigenesis in non-small cell lung cancer (NSCLC) (5).

Acyl-CoA synthetase long-chain family member 4 (ACSL4) preferentially catalyzes the formation of arachidonoyl-coenzyme A (AA-CoA) by inserting coenzyme A (CoA) into arachidonic acid (AA) (6). ACSL4-catalyzed acyl-CoAs also participate in the regulation of steroidogenesis (7), eicosanoid biosynthesis (8), and phospholipid remodeling (9). ACSL4 is an essential enzyme for the conversion of two key ferroptosis-inducing signals, oxidized arachidonic and adrenic phosphatidylethanolamines (10,11). Genome-wide CRISPR/Cas9-based genetic screens have demonstrated that ACSL4 is an essential component for ferroptosis execution (11), and genetic or pharmacological inhibition of ACSL4 can initiate a specific anti-ferroptotic rescue pathway (10). ACSL4 expression is upregulated in ferroptosis-sensitive cancer cells compared with ferroptosis-resistant cells (12) and has been shown to predict sensitivity to ferroptosis in a panel of basal-like breast cancer cell lines (11). Moreover, high ACSL4 protein expression in hepatocellular carcinoma (HCC) clinical tissue specimens is associated with improved patient outcomes after sorafenib treatment and could serve as a predictive biomarker (13).

LPCAT1 (lysophosphatidylcholine acyltransferase 1), an enzyme that functions in phospholipid metabolism and remodeling, has been reported to be highly expressed and to play a tumor-promoting role in multiple human cancers. Overexpression of LPCAT1 is linked to poor prognosis in breast cancer and hepatocellular carcinoma (HCC) (14,15). In cervical cancer, knockdown of LPCAT1 reduces proliferation, migration, and invasion of cancer cells, and LPCAT1 deletion reduces tumor growth and metastasis in mice through Jak2/Stat3 signaling (16). In endometrial cancer, LPCAT1 enhances stemness and metastasis through TGF-β signaling (17). In NSCLC, LPCAT1 upregulates EGFR/PI3K/Akt signaling, promoting resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) (18).

LPCAT3 (lysophosphatidylcholine acyltransferase 3), also called MBOAT5, is part of the LPCAT family that plays an important role in lipid metabolism (19,20). Elevated expression of LPCAT3 is associated with the iron-dependent cell death process of ferroptosis, characterized by an increase in lipid peroxidation (21). LPCAT3 inhibitors have shown a partial protection from ferroptosis (22).

Sterol regulatory element–binding proteins (SREBPs) are basic helix-loop-helix–leucine zipper (bHLH-Zip) transcription factors (23,24). Studies show that SREBP-1-dependent fatty acid homeostasis has a critical role in promoting the pro-tumor phenotype of M2-like tumor-associated macrophages (TAMs), and inhibition of SREBP-1 enhances the efficacy of immune checkpoint blockade (25). In addition, suppression of cholesterol biosynthesis by statins stimulates SREBP-1 activation and, therefore, induces TGF-β signaling, promoting the epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma (26).