代谢重编程和细胞衰老极大地促进了癌症复发。在衰老和治疗的前列腺中，癌细胞持续积累的衰老相关分泌表型（SASP）常常限制患者的总体生存。利用单酰基甘油脂肪酶 (MGLL) 上调来对抗细胞和多西紫杉醇诱导的 SASP 的新型策略疗法可能会克服前列腺癌 (PCa) 的这一临床挑战。通过 TCGA PCa 数据集和我们的单中心队列中脂肪酸 (FA) 代谢特征基因的初步比较表达和生存分析筛选，检测到 MGLL 在恶性前列腺组织中下调，其低表达预示着更差的无进展生存和总生存。从功能上来说，MGLL的过度表达主要抑制NF-κB驱动的SASP（N-SASP），这主要限制癌细胞旁分泌和自分泌的致瘤方式以及相应的细胞衰老。进一步研究代谢物，我们确定 MGLL 组成型表达可以防止脂质积累，更好地减少代谢物，从而下调 ATP 水平。过度表达的 MGLL 抑制 IκBα 磷酸化、NF-κB p65 磷酸化和 NF-κB 核转位，从而使 NF-κB 转录活性失活，并部分通过降低 ATP 水平来抑制 N-SASP。临床前，MGLL 过表达和多西他赛化疗的联合治疗可显着延缓小鼠模型中的肿瘤进展。总而言之，我们的研究结果确定 MGLL 是脂肪酶相关 N-SASP 抑制的开关，并为促进 PCa 中多西他赛疗效提供了潜在的候选药物。© 2024。作者获得 Springer Nature Limited 的独家许可。

Metabolic reprogramming and cellular senescence greatly contribute to cancer relapse and recurrence. In aging and treated prostate, persistent accumulating senescence-associated secretory phenotype (SASP) of cancer cells often limits the overall survival of patients. Novel strategic therapy with monoacylglycerol lipase (MGLL) upregulation that counters the cellular and docetaxel induced SASP might overcome this clinical challenge in prostate cancer (PCa). With primary comparative expression and survival analysis screening of fatty acid (FA) metabolism signature genes in the TCGA PCa dataset and our single center cohort, MGLL was detected to be downregulated in malignancy prostate tissues and its low expression predicted worse progression-free and overall survival. Functionally, overexpression of MGLL mainly suppresses NF-κB-driven SASP (N-SASP) which mostly restricts the cancer cell paracrine and autocrine tumorigenic manners and the corresponding cellular senescence. Further investigating metabolites, we determined that MGLL constitutive expression prevents lipid accumulation, decreases metabolites preferably, and consequently downregulates ATP levels. Overexpressed MGLL inhibited IκBα phosphorylation, NF-κB p65 phosphorylation, and NF-κB nuclear translocation to deactivate NF-κB transcriptional activities, and be responsible for the repressed N-SASP, partially through reducing ATP levels. Preclinically, combinational treatment with MGLL overexpression and docetaxel chemotherapy dramatically delays tumor progression in mouse models. Taken together, our findings identify MGLL as a switch for lipase-related N-SASP suppression and provide a potential drug candidate for promoting docetaxel efficacy in PCa.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.