Mechanism of action of lipid metabolic reprogramming in gemcitabine resistance of pancreatic ductal adenocarcinoma and related targeted intervention strategies
- VernacularTitle:脂质代谢重编程在胰腺导管腺癌吉西他滨耐药中的作用机制及相关靶向干预策略
- Author:
Kailian ZHENG
1
;
Huan WANG
1
;
Suizhi GAO
1
;
Jiaxin ZHANG
1
;
Lin XIAO
1
;
Leshui ZHANG
1
;
Gang JIN
1
Author Information
- Publication Type:Review
- Keywords: Pancreatic Neoplasms; Lipid Metabolism; Gemcitabine
- From: Journal of Clinical Hepatology 2026;42(9):2251-2256
- CountryChina
- Language:Chinese
- Abstract: Pancreatic ductal adenocarcinoma （PDAC） has an extremely poor prognosis， and resistance to gemcitabine is one of the key reasons for treatment failure， with an underlying mechanism closely associated with lipid metabolic reprogramming in tumor cells. This article aims to systematically elaborate on the multidimensional drug resistance network constructed by such reprogramming and the feasibility of targeted intervention. Lipid metabolic reprogramming comprehensively remodels the metabolic homeostasis of PDAC cells by enhancing lipid uptake， de novo synthesis， storage， and oxidative catabolism in a synergistic manner. This process alters membrane lipid composition to impede drug influx and promote efflux， thereby reducing intracellular drug concentration. Meanwhile， it activates pathways involving sterol regulatory element-binding protein and peroxisome proliferator-activated receptor δ， couples lipid synthesis with cell survival， stemness， and anti-apoptotic capacity， and synergizes with autophagy to provide survival support through “lipophagy”. In addition， it reshapes the tumor microenvironment through “lipid hijacking” and the secretion of immunosuppressive mediators. Based on the above mechanisms， targeting key lipid metabolic enzymes （such as fatty acid synthase， stearoyl-CoA desaturase， carnitine palmitoyltransferase 1） or their upstream regulators has shown certain potential in reversing such drug resistance in preclinical studies. Although clinical translation faces the challenges such as systemic toxicity， metabolic redundancy in tumors， and patient heterogeneity， the development of biomarkers， intelligent drug delivery systems， and combined therapies may provide new ideas for overcoming drug resistance.
