文献类型：期刊文献

英文题名：From Metabolic Reprogramming to Lactylation: Targeting Dilemmas and Breakthrough Directions in Colorectal Cancer

作者：Zhang, Xin[1,2];Li, Zhao-Huan[1,2];Zhao, Jing-Wen[3];Du, Jie[4,5];Gao, Feng[1,2]

第一作者：张欣;Zhang, Xin

通信作者：Gao, F[1];Gao, F[2]

机构：[1]Gansu Univ Chinese Med, Sch Clin Chinese Med, Lanzhou 730101, Peoples R China;[2]GansuProvincial Cent Hosp, Dept Colorectal & Anal Surg, Lanzhou 730050, Peoples R China;[3]Xian Hosp Tradit Chinese Med, Anorectal Dept, Xian 710021, Peoples R China;[4]Sichuan Univ, West China Sch Publ Hlth, Dept Urol & Pelv Surg & Androl, Chengdu 610041, Peoples R China;[5]Sichuan Univ, West China Hosp 4, Chengdu 610041, Peoples R China

第一机构：甘肃中医药大学

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Sch Clin Chinese Med, Lanzhou 730101, Peoples R China;[2]corresponding author), GansuProvincial Cent Hosp, Dept Colorectal & Anal Surg, Lanzhou 730050, Peoples R China.|[10735]甘肃中医药大学;

年份：2026

卷号：53

期号：8

起止页码：2123

外文期刊名：PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001862620000008)】；

基金：* This work was supported by grants from Department of Science and Technology of Gansu Province (23JRRA539) and Nanchong Science and Technology Program (23YYJCYJ0084) .

语种：英文

外文关键词：colorectal cancer; lactate homeostasis; lactylation regulatory network; targeting lactylation

摘要：Colorectal cancer (CRC) is characterized by persistently high incidence and mortality. Current therapies are limited by drug resistance and modest patient benefit, underscoring the urgent need for new perspectives rooted in tumor biology. The unique metabolic landscape of CRC makes it an ideal model in which to dissect the pathological roles of lactylation regulatory networks: microsatellite-stable (MSS) CRC, which accounts for approximately 85% of cases, concurrently upregulates glycolysis and oxidative phosphorylation, engaging in intense metabolic competition with immune cells; the intratumoral lactate pool exhibits a distinctive "dual-source supply" feature-in addition to tumor-intrinsic glycolysis, substantial exogenous lactate is provided by gut microbiota dysbiosis and by colonizing bacteria within liver metastases; high-frequency oncogenic mutations and lactylation modifications establish a feed-forward circuit of "oncogene-driven lactate accumulationlactylation-facilitated tumor progression". Moreover, MSS CRC displays near-complete unresponsiveness to immune checkpoint inhibitors, a phenomenon underpinned by multiple immune evasion mechanisms mediated by lactate and lactylation. Lactate metabolism is a hallmark of metabolic reprogramming in cancer. Lactate homeostasis provides tumor cells with metabolic substrates, modulates redox status, and regulates fatty acid metabolism to promote malignant progression. Notably, lactate can drive lactylation-an emerging post-translational modification (PTM) in which lactyl groups are attached to lysine residues, dynamically governing gene transcription and protein function and thereby establishing a bridge between metabolism and epigenetics. Lactate and lactylation form a multidimensional, coordinated network: lactylation of key metabolic enzymes such as LDHA reinforces a positive feedback loop that sustains lactate production; lactylation of upstream transcription factors such as HIF-1 alpha drives metabolic reprogramming; furthermore, lactylation engages in crosstalk with m6A and m5C RNA modifications as well as with other PTMs such as acetylation, profoundly reshaping cellular behavior. In CRC, histone lactylation drives malignant phenotypes by activating immunosuppressive programs, inhibiting ferroptosis, and promoting invasion and migration; non-histone lactylation accelerates translation elongation, stabilizes beta-catenin, maintains redox homeostasis, and prevents PD-L1 degradation, thereby facilitating tumor progression. Lactylation-related gene signatures have demonstrated potential for prognostic stratification. Therapeutic strategies targeting the lactylation network range from upstream metabolic intervention to modulation of the modifying enzymes and direct blockade of lactylation modifications, forming a hierarchical interventional framework. However, current evidence derives predominantly from cell lines and xenograft models, and a causal relationship between lactylation and malignant progression in CRC has yet to be rigorously established. Whether inhibition of lactylation can alter CRC phenotypes independently of metabolic alterations and acetylation fluctuations remains a central unanswered question in the field. This review systematically examines the research progress and translational challenges surrounding lactylation regulatory networks, aiming to provide a circumspect assessment to inform the development of novel therapeutic strategies for CRC.