Initially characterized as an epigenetic marker for transcriptional regulation, lysine lactylation is now recognized as a pervasive posttranslational modification with extensive functions beyond those associated with chromatin. Recent methodological advances in the resolution of stereoisomeric dynamics have established L-lactylation as the predominant glycolysis-derived functional form, providing a metabolic switch that couples glycolytic flux to oncogenic signaling. Here, we provide a comprehensive overview of non-histone L-lactylation in cancer biology. We define the spatially compartmentalized catalytic network governing this process, detailing how nuclear EP300/CBP, cytosolic AARS1, and mitochondrial AARS2 mediate stereospecific targeted modifications. At the molecular level, non-histone L-lactylation alters protein biophysics via charge neutralization, steric hindrance, and interface remodeling. These physicochemical alterations govern fundamental enzymatic kinetics, complex assembly, subcellular trafficking, and proteasomal degradation processes. Through primarily transcription-independent mechanisms, L-lactylation enables cancer cells to sustain metabolic flexibility, promote the repair of damaged DNA, and foster an immunosuppressive tumor microenvironment. Because tumors exploit these regulatory networks to drive adaptive resistance across diverse therapeutic modalities, we examine current strategies for pharmacological intervention. Finally, we highlight critical unresolved questions in this field. Notably, the identification of lactylation-specific readers and the development of stereoisomer-resolved chemobiological tools will be essential to fully leverage this metabolism–modification axis for cancer therapy.
Ying-Ying Guo, Lanyang Gao, Shundan Li et al.· Molecular Cancer· 0 citations
BACKGROUND
Colorectal liver metastasis (CRLM) remains the primary cause of mortality in patients with colorectal cancer (CRC). Despite its clinical significance, the complex molecular networks and microenvironmental dynamics driving CRLM remain incompletely understood. Identifying robust prognostic biomarkers and elucidating their underlying mechanisms are of critical importance for advancing targeted interventions.
METHODS
We integrated Weighted gene co-expression network analysis (WGCNA) with differential expression profiling to identify the CRLM-associated hub genes. The clinical relevance and spatial expression of the identified target, SERPING1, were validated in human CRC and CRLM tissue cohorts. In vitro functional assays (siRNA knockdown) and transcriptomic enrichment analyses were performed to evaluate the impact of SERPING1 on malignant epithelial phenotypes. Finally, Single-cell RNA sequencing (scRNA-seq) and immune infiltration algorithms were utilized to delineate its distribution within the tumor microenvironment (TME).
RESULTS
SERPING1 was identified as a critical prognostic hub gene, with its elevated expression significantly correlating with poor patient survival and exhibiting a stepwise upregulation along the primary-to-metastasis axis in clinical tissues. In vitro, silencing SERPING1 attenuated the proliferative, migratory, and invasive capacities of CRC cells. This was accompanied by a molecular shift away from the epithelial-mesenchymal transition (EMT) program, supported by the enrichment of classical pro-metastatic cascades. Crucially, scRNA-seq and microenvironmental analysis revealed that in vivo, SERPING1 is predominantly enriched within cancer-associated fibroblasts (CAFs), establishing a strong correlation with stromal infiltration.
CONCLUSIONS
These findings suggest that SERPING1 serves as a crucial molecular nexus in CRLM, potentially facilitating disease dissemination by supporting malignant EMT phenotypes and participating in stromal TME remodeling. Consequently, SERPING1 represents a promising biomarker and a potential therapeutic target for mitigating CRLM.
Wenhao Yu, Boyuan Gu, Zhiwei Huang et al.· Biochimica et Biophysica Act...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
