bims-meprid 2025-02-16 papers

Cell Rep. 2025 Feb 10. pii: S2211-1247(25)00055-5. [Epub ahead of print]44(2): 115284

Acetyl-CoA synthesis in the skin is a key determinant of systemic lipid homeostasis.

Phuong T T Nguyen, Mia Shiue, Nina Kuprasertkul, Pedro Costa-Pinheiro, Luke T Izzo, Laura V Pinheiro, Hayley A Affronti, Gabriel Gugiu, Shivani Ghaisas, Joyce Y Liu, Jordan C Harris, Charles W Bradley, John T Seykora, Xiaolu Yang, Taku Kambayashi, Clementina Mesaros, Brian C Capell, Kathryn E Wellen.

ATP-citrate lyase (ACLY) generates cytosolic acetyl-coenzyme A (acetyl-CoA) for lipid synthesis and is a promising therapeutic target in diseases with altered lipid metabolism. Here, we developed inducible whole-body Acly-knockout mice to determine the requirement for ACLY in normal tissue functions, uncovering its crucial role in skin homeostasis. ACLY-deficient skin upregulates the acetyl-CoA synthetase ACSS2; deletion of both Acly and Acss2 from the skin exacerbates skin abnormalities, with differential effects on two major lipid-producing skin compartments. While the epidermis is depleted of barrier lipids, the sebaceous glands increase production of sebum, supplied at least in part by circulating fatty acids and coinciding with adipose lipolysis and fat depletion. Dietary fat supplementation further boosts sebum production and partially rescues both the lipoatrophy and the aberrant skin phenotypes. The data establish a critical role for cytosolic acetyl-CoA synthesis in maintaining skin barrier integrity and highlight the skin as a key organ in systemic lipid regulation.

Keywords: ACLY; ACSS2; CP: Metabolism; acetyl-CoA; adipose; epidermis; lipid metabolism; sebaceous glands; skin; skin barrier

DOI: https://doi.org/10.1016/j.celrep.2025.115284

Acta Pharmacol Sin. 2025 Feb 12.

Acyl-CoA thioesterase 8 induces gemcitabine resistance via regulation of lipid metabolism and antiferroptotic activity in pancreatic ductal adenocarcinoma.

Bo-Rui Li, Ting Wang, Hai-Feng Hu, Di Wu, Chen-Jie Zhou, Shun-Rong Ji, Qi-Feng Zhuo, Zheng Li, Zhi-Liang Wang, Gui-Xiong Fan, De-Sheng Jing, Chong-Yuan Yu, Yi Qin, Xue-Min Chen, Jun-Feng Xu, Xiao-Wu Xu.

Pancreatic ductal adenocarcinoma (PDAC) comprises a group of highly malignant tumors of the pancreas. Metabolic reprogramming in tumors plays a pivotal role in promoting cancer progression. However, little is known about the metabolic alterations in tumors that drive cancer drug resistance in patients with PDAC. Here, we identified acyl-CoA thioesterase 8 (ACOT8) as a key player in driving PDAC gemcitabine (GEM) resistance. The expression of ACOT8 is significantly upregulated in GEM-resistant PDAC tissues and is closely associated with poor survival in patients with PDAC. Gain- and loss-of-function studies have shown that ACOT8 drives PDAC GEM resistance both in vitro and in vivo. Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. The combination of orlistat, an ACOT8 inhibitor, and GEM significantly inhibited tumor growth in PDAC organoid and mouse models. This study reveals the biological importance of ACOT8 and provides a potential combination therapy for treating patients with advanced GEM-resistant PDAC.

DOI: https://doi.org/10.1038/s41401-025-01477-y

Adv Sci (Weinh). 2025 Feb 14. e2416467

ACAT1-Mediated ME2 Acetylation Drives Chemoresistance in Ovarian Cancer by Linking Glutaminolysis to Lactate Production.

Cuimiao Zheng, Hao Tan, Gang Niu, Xi Huang, Jingyi Lu, Siqi Chen, Haoyuan Li, Jiayu Zhu, Zhou Zhou, Manman Xu, Chaoyun Pan, Junxiu Liu, Jie Li.

Lactate derived from aerobic glycolysis is crucial for DNA damage repair and chemoresistance. Nevertheless, it is frequently noted that cancer cells depend on glutaminolysis to replenish essential metabolites. Whether and how glutaminolysis might enhance lactate production and facilitate DNA repair in cancer cells remains unknown. Here, it is shown that malate enzyme 2 (ME2), which metabolizes glutamine-derived malate to pyruvate, contributes to lactate production and chemotherapy resistance in ovarian cancer. Mechanistically, chemotherapy reduces the expression of glucose transporters and impairs glucose uptake in cancer cells. The resultant decrease in intracellular glucose levels triggers the acetylation of ME2 at lysine 156 by ACAT1, which in turn potentiates ME2 enzyme activity and facilitates lactate production from glutamine. ME2-derived lactate contributes to the development of acquired chemoresistance in cancer cells subjected to prolonged chemotherapy, primarily by facilitating the lactylation of proteins involved in homologous recombination repair. Targeting ACAT1 to inhibit ME2 acetylation effectively reduced chemoresistance in both in vitro and in vivo models. These findings underscore the significance of acetylated ME2-mediated lactate production from glutamine in chemoresistance, particularly under conditions of reduced intracellular glucose within cancer cell, thereby complementing the Warburg effect and offering new perspectives on the metabolic links to chemotherapy resistance.

Keywords: ME2; acetylation; lactylation; platinum resistance

DOI: https://doi.org/10.1002/advs.202416467