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

郑楷炼; 王欢; 高绥之; 张佳鑫; 肖麟; 张乐水; 金钢

doi:10.12449/JCH260934

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

DOI: 10.12449/JCH260934

海军军医大学长海医院肝胆胰脾外科，上海 200433

基金项目:

国家科技重大专项2025年度新型组织方式项目 (2025ZD0552306);

海军军医大学校级基础医学研究课题面上孵化项目 (2022MS013)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：郑楷炼负责设计论文框架，撰写论文；王欢和高绥之负责拟定写作思路，修改论文；张佳鑫、肖麟和张乐水负责查找文献，制作图表；金钢负责指导文章撰写并最后定稿。

详细信息

通信作者:
金钢， jingang@smmu.edu.cn （ORCID： 0000-0001-6713-1185）

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出版历程
- 收稿日期: 2026-01-14
- 录用日期: 2026-03-09
- 出版日期: 2026-09-25

Mechanism of action of lipid metabolic reprogramming in gemcitabine resistance of pancreatic ductal adenocarcinoma and related targeted intervention strategies

Department of Hepatobiliary，Pancreatic and Splenic Surgery，Changhai Hospital，Navy Medical University，Shanghai 200433，China

Research funding:

National Science and Technology Major Project, FY2025 New Organizational Modality (2025ZD0552306);

General Incubation Program of Basic Medical Research of Naval Medical University (2022MS013)

More Information

Corresponding author: Jin Gang， jingang@smmu.edu.cn （ORCID： 0000-0001-6713-1185）

摘要

摘要: 胰腺导管腺癌（PDAC）预后极差，吉西他滨耐药是导致其治疗失败的关键原因之一，其核心机制可能与肿瘤细胞的脂质代谢重编程密切相关。本文旨在系统阐述这一重编程构建的多维度耐药网络，及其靶向干预的可行性。脂质代谢重编程全面重构PDAC细胞的代谢稳态，通过脂质摄取、内源性合成、储存与氧化分解等协同增强实现重塑。该过程改变膜脂组成，破坏药物内流并增强外排，降低胞内药物浓度。同时，激活固醇调节元件结合蛋白、过氧化物酶体增殖物激活受体δ等通路，将脂质合成与细胞生存、干性及抗凋亡能力相耦合，并与自噬过程协同，通过“脂自噬”提供生存支持。此外，还通过“脂质劫持”及分泌免疫抑制性介质重塑肿瘤微环境。基于上述机制，靶向抑制脂肪酸合成酶、硬脂酰辅酶A去饱和酶及肉碱棕榈酰转移酶1等脂质代谢关键酶或其上游调控因子，在临床前研究中已显示出逆转耐药的潜力。尽管临床转化面临全身毒性、肿瘤代谢冗余及患者异质性等问题，但通过开发生物标志物、智能递药系统及联合治疗策略，有望为克服耐药提供新的思路。
- 胰腺肿瘤 /
- 脂质代谢 /
- 吉西他滨
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.
- Pancreatic Neoplasms /
- Lipid Metabolism /
- Gemcitabine

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参考文献(48)

[1]	Siegel R L, Giaquinto A N, Jemal A. Cancer statistics, 2024[J]. CA Cancer J Clin, 2024, 74( 1): 12- 49. DOI: 10.3322/caac.21820.
[2]	Sung H, Ferlay J, Siegel R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71( 3): 209- 249. DOI: 10.3322/caac.21660.
[3]	van Cutsem E, Tempero M A, Sigal D, et al. Randomized phase III trial of pegvorhyaluronidase Alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma[J]. J Clin Oncol, 2020, 38( 27): 3185- 3194. DOI: 10.1200/JCO.20.00590.
[4]	Kamphorst J J, Nofal M, Commisso C, et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein[J]. Cancer Res, 2015, 75( 3): 544- 553. DOI: 10.1158/0008-5472.CAN-14-2211.
[5]	Zhang J Y, Kong X Q, Zhou B Y, et al. Metabolic reprogramming of drug resistance in pancreatic cancer: Mechanisms and effects[J]. Mol Aspects Med, 2025, 103: 101368. DOI: 10.1016/j.mam.2025.101368.
[6]	Nicolson G L, Ash M E. Lipid replacement therapy: A natural medicine approach to replacing damaged lipids in cellular membranes and organelles and restoring function[J]. Biochim Biophys Acta BBA Biomembr, 2014, 1838( 6): 1657- 1679. DOI: 10.1016/j.bbamem.2013.11.010.
[7]	Pascual G, Avgustinova A, Mejetta S, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36[J]. Nature, 2017, 541( 7635): 41- 45. DOI: 10.1038/nature20791.
[8]	Auciello F R, Bulusu V, Oon C, et al. A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression[J]. Cancer Discov, 2019, 9( 5): 617- 627. DOI: 10.1158/2159-8290.CD-18-1212.
[9]	Bian X L, Liu R, Meng Y, et al. Lipid metabolism and cancer[J]. J Exp Med, 2021, 218: e20201606. DOI: 10.1084/jem.20201606.
[10]	Olzmann J A, Carvalho P. Dynamics and functions of lipid droplets[J]. Nat Rev Mol Cell Biol, 2019, 20( 3): 137- 155. DOI: 10.1038/s41580-018-0085-z.
[11]	Lin Y H, Zhang X, Wang Y H, et al. LPCAT2-mediated lipid droplet production supports pancreatic cancer chemoresistance and cell motility[J]. Int Immunopharmacol, 2024, 139: 112681. DOI: 10.1016/j.intimp.2024.112681.
[12]	Shin S C, Thomas D, Radhakrishnan P, et al. Invasive phenotype induced by low extracellular pH requires mitochondria dependent metabolic flexibility[J]. Biochem Biophys Res Commun, 2020. DOI: 10.1016/j.bbrc.2020.02.018.[ Online ahead of print]
[13]	Min J Y, Kim D H. Stearoyl-CoA desaturase 1 as a therapeutic biomarker: Focusing on cancer stem cells[J]. Int J Mol Sci, 2023, 24( 10): 8951. DOI: 10.3390/ijms24108951.
[14]	Zhou C C, Feng Z Y, Qian W K, et al. Elevated SREBP1 accelerates the initiation and growth of pancreatic cancer by targeting SOX9[J]. Biol Direct, 2025, 20( 1): 6. DOI: 10.1186/s13062-025-00595-1.
[15]	Smith R C, Bulanadi J C, Gill A J, et al. Pancreatic adenocarcinoma preferentially takes up and is suppressed by synthetic nanoparticles carrying apolipoprotein A-II and a lipid gemcitabine prodrug in mice[J]. Cancer Lett, 2020, 495: 112- 122. DOI: 10.1016/j.canlet.2020.08.045.
[16]	Websdale A, Kiew Y, Chalmers P, et al. Pharmacologic and genetic inhibition of cholesterol esterification enzymes reduces tumour burden: A systematic review and meta-analysis of preclinical models[J]. Biochem Pharmacol, 2022, 196: 114731. DOI: 10.1016/j.bcp.2021.114731.
[17]	Oberle R, Kührer K, Österreicher T, et al. The HDL particle composition determines its antitumor activity in pancreatic cancer[J]. Life Sci Alliance, 2022, 5( 9): e202101317. DOI: 10.26508/lsa.202101317.
[18]	Konaté M M, Krushkal J, Li M C, et al. Insights into gemcitabine resistance in pancreatic cancer: Association with metabolic reprogramming and TP53 pathogenicity in patient derived xenografts[J]. J Transl Med, 2024, 22( 1): 733. DOI: 10.1186/s12967-024-05528-6.
[19]	Mascaraque M, Courtois S, Royo-García A, et al. Fatty acid oxidation is critical for the tumorigenic potential and chemoresistance of pancreatic cancer stem cells[J]. J Transl Med, 2024, 22( 1): 797. DOI: 10.1186/s12967-024-05598-6.
[20]	Pakhira S, Kundu S, Roy S S. The role of fatty acid oxidation in metabolic crosstalk between tumor cells and associated factors in the microenvironment[J]. Biochim Biophys Acta BBA Rev Cancer, 2025, 1880( 6): 189447. DOI: 10.1016/j.bbcan.2025.189447.
[21]	Qiao J C, Yu Z C, Zhou H, et al. The pentose phosphate pathway: From mechanisms to implications for gastrointestinal cancers[J]. Int J Mol Sci, 2025, 26( 2): 610. DOI: 10.3390/ijms26020610.
[22]	Hu Q, Jiang C, Qin Y, et al. Pentose phosphate recycling driven by Gli1 contributes to chemotherapy resistance in cancer cells[J]. Cancer Lett, 2025, 618: 217633. DOI: 10.1016/j.canlet.2025.217633.
[23]	Pérez-Torras S, García-Manteiga J, Mercadé E, et al. Adenoviral-mediated overexpression of human equilibrative nucleoside transporter 1(hENT1) enhances gemcitabine response in human pancreatic cancer[J]. Biochem Pharmacol, 2008, 76( 3): 322- 329. DOI: 10.1016/j.bcp.2008.05.011.
[24]	Wang R X, Gao C H, Fan Z Y, et al. Mitochondria-centric lipid metabolism and inter-organelle crosstalk in pancreatic Cancer: Unveiling novel therapies[J]. Cancer Lett, 2025, 632: 217965. DOI: 10.1016/j.canlet.2025.217965.
[25]	Hopper-Borge E, Xu X, Shen T, et al. Human multidrug resistance protein 7(ABCC10) is a resistance factor for nucleoside analogues and epothilone B[J]. Cancer Res, 2009, 69( 1): 178- 184. DOI: 10.1158/0008-5472.CAN-08-1420.
[26]	Guo L L, He Y, Xin H. GDF15 promotes the resistance of epithelial ovarian cancer cells to gemcitabine via DHCR24-mediated cholesterol metabolism to elevate ABCB1 and ABCC1 levels in lipid rafts[J]. Am J Cancer Res, 2025, 15( 2): 452- 469. DOI: 10.62347/KYIY8286.
[27]	Liu G Y, Yang D X, Meng J, et al. The combination of gemcitabine and albumin-bound paclitaxel effectively inhibits de novo lipogenesis in pancreatic cancer cells by targeting the AMPK/SREBP1 pathway[J]. Biochem Pharmacol, 2025, 232: 116721. DOI: 10.1016/j.bcp.2024.116721.
[28]	Lei Y, Cai S, Zhang J K, et al. The role and mechanism of fatty acid oxidation in cancer drug resistance[J]. Cell Death Discov, 2025, 11( 1): 277. DOI: 10.1038/s41420-025-02554-1.
[29]	Meng Y L, Bian L, Zhang M C, et al. ISG15 promotes progression and gemcitabine resistance of pancreatic cancer cells through ATG7[J]. Int J Biol Sci, 2024, 20( 4): 1180- 1193. DOI: 10.7150/ijbs.85424.
[30]	Huang X T, Chen J, Zhu E L, et al. Positive feedback loop of histone lactylation-driven HNRNPC promotes autophagy to confer pancreatic ductal adenocarcinoma gemcitabine resistance[J]. Adv Sci, 2026, 13( 8): e10483. DOI: 10.1002/advs.202510483.
[31]	Du X Z, Yu R Z, Yan C G, et al. USP10 promotes the progression and attenuates gemcitabine chemotherapy sensitivity via stabilizing PLK1 in PDAC[J]. Cell Death Dis, 2025, 16: 449. DOI: 10.1038/s41419-025-07757-z.
[32]	Zhou C F, Yi C H, Yi Y X, et al. LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes[J]. Mol Cancer, 2020, 19( 1): 118. DOI: 10.1186/s12943-020-01237-y.
[33]	Baldwin J G, Silveira C R F, Gattinoni L. Restoring the supply lines: Removing roadblocks to fatty acid uptake enhances T cell-driven cancer fight[J]. Sig Transduct Target Ther, 2025, 10( 1): 53. DOI: 10.1038/s41392-025-02151-9.
[34]	Biffi G, Oni T E, Spielman B, et al. IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma[J]. Cancer Discov, 2019, 9( 2): 282- 301. DOI: 10.1158/2159-8290.CD-18-0710.
[35]	Cao Y H. Adipocyte and lipid metabolism in cancer drug resistance[J]. J Clin Invest, 2019, 129( 8): 3006- 3017. DOI: 10.1172/JCI127201.
[36]	Tadros S, Shukla S K, King R J, et al. De novo lipid synthesis facilitates gemcitabine resistance through endoplasmic reticulum stress in pancreatic cancer[J]. Cancer Res, 2017, 77( 20): 5503- 5517. DOI: 10.1158/0008-5472.CAN-16-3062.
[37]	Liu S, Kang S B, Lin N, et al. The TET3/GATA6 axis drives lipid metabolism and therapeutic vulnerabilities in pancreatic ductal adenocarcinoma[J]. Adv Sci(Weinh), 2025, 12( 37): e01774. DOI: 10.1002/advs.202501774.
[38]	Hackney A B, Chung W Y, Isherwood J, et al. Stearoyl-CoA desaturase 1 inhibitor supplemented with gemcitabine treatment reduces the viability and fatty acid content of pancreatic cancer cells in vitro[J]. J Pancreatol, 2021, 4: 170- 177. DOI: 10.1097/JP9.0000000000000082.
[39]	Cenigaonandia-Campillo A, Garcia-Bautista A, Rio-Vilariño A, et al. Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest[J]. Mol Oncol, 2024, 18( 9): 2212- 2233. DOI: 10.1002/1878-0261.13616.
[40]	Luo J, Hong Y, Tao X, et al. An indispensable role of CPT-1a to survive cancer cells during energy stress through rewiring cancer metabolism[J]. Tumour Biol, 2016, 37: 15795- 15804. DOI: 10.1007/s13277-016-5382-6.
[41]	Tang R, Xu J, Wang W, et al. Targeting neoadjuvant chemotherapy-induced metabolic reprogramming in pancreatic cancer promotes anti-tumor immunity and chemo-response[J]. Cell Rep Med, 2023, 4( 10): 101234. DOI: 10.1016/j.xcrm.2023.101234.
[42]	Zhou C, Qian W, Ma J, et al. Resveratrol enhances the chemotherapeutic response and reverses the stemness induced by gemcitabine in pancreatic cancer cells via targeting SREBP1[J]. Cell Prolif, 2019, 52( 1): e12514. DOI: 10.1111/cpr.12514.
[43]	Lao M Y, Zhang X Z, Li Z J, et al. Lipid metabolism reprograming by SREBP1-PCSK9 targeting sensitizes pancreatic cancer to immunochemotherapy[J]. Cancer Commun(Lond), 2025, 45( 8): 1010- 1037. DOI: 10.1002/cac2.70038.
[44]	Parejo-Alonso B, Barneda D, Trabulo S, et al. PPARδ orchestrates a prometastatic metabolic response to microenvironmental cues in pancreatic cancer[J]. Cancer Res, 2025, 85( 17): 3275- 3291. DOI: 10.1158/0008-5472.CAN-24-3475.
[45]	Nagaraju G P, Saddala M S, Foote J B, et al. Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine[J]. Cell Rep Med, 2025, 6( 1): 101881. DOI: 10.1016/j.xcrm.2024.101881.
[46]	Tang H L, Xue Y N, Li B W, et al. Membrane-camouflaged supramolecular nanoparticles for co-delivery of chemotherapeutic and molecular-targeted drugs with siRNA against patient-derived pancreatic carcinoma[J]. Acta Pharm Sin B, 2022, 12( 8): 3410- 3426. DOI: 10.1016/j.apsb.2022.02.007.
[47]	Escalera-Anzola S, Rosado M, Yang Y C, et al. Breakthroughs in nanoparticle-based strategies for pancreatic cancer terapy[J]. Biochem Pharmacol, 2025, 232: 116685. DOI: 10.1016/j.bcp.2024.116685.
[48]	Yang L F, TeSlaa T, Ng S, et al. Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth[J]. Med, 2022, 3( 2): 119- 136. DOI: 10.1016/j.medj.2021.12.008.