circMTHFD1L-driven lipid metabolism in Cancer-associated fibroblasts confers oxaliplatin resistance in pancreatic cancer through O-GlcNAcylation-dependent chromatin recruitment of Ku70.

Abstract

Platinum-based chemotherapy resistance severely limits therapeutic efficacy and survival in pancreatic ductal adenocarcinoma (PDAC), yet the role of cancer-associated fibroblasts (CAFs) in driving this resistance remains elusive. We screened and validated circMTHFD1L (hsa_circ_0078269) as a stromal circRNA that is markedly upregulated in CAFs from oxaliplatin-resistance (OXA-R) PDAC, and its expression was correlating with poor patient survival. Gain- and loss-of-function assays demonstrated that circMTHFD1L in CAFs is necessary to confer oxaliplatin resistance, primarily through metabolic reprogramming of fatty acid (FA) biosynthesis. Mechanistically, circMTHFD1L directly interacts with the key FA synthesis enzyme acetyl-CoA carboxylase 1 (ACC1), thereby inhibiting its ubiquitination-mediated degradation and enhancing FA production. Tumor cells uptake FA from circMTHFD1L-high CAFs, resulting in increased intracellular uridine diphosphate N-acetylglucosamine availability, a key substrate for O-GlcNAcylation. This metabolic reprogramming promotes Ku70 O-GlcNAcylation and chromatin recruitment, thereby enhancing non-homologous end joining repair efficiency and driving resistance to oxaliplatin in PDAC. Therapeutic targeting of the circMTHFD1L/ACC1 axis in vivo resulted in marked suppression of tumor growth and restored sensitivity to oxaliplatin in orthotopic models. Additionally, we engineered a lipid nanoparticle-based delivery system for sh-circMTHFD1L plasmids and demonstrated that it enhanced the therapeutic efficacy of oxaliplatin in a patient-derived xenograft model. Clinically, high circMTHFD1L expression was positively correlated with ACC1 abundance and served as a poor prognostic prognosis. Collectively, our study reveals that CAF-derived circMTHFD1L drives oxaliplatin resistance in PDAC by stabilizing ACC1 to reprogram FA metabolism and promote Ku70 O-GlcNAcylation, identifying the circMTHFD1L/ACC1/Ku70 axis as a promising target to overcome chemoresistance.