Low Serum LDL-C Is Associated with Poorer Overall Survival and Lipid-Related Molecular Features in Colorectal Cancer

Background/Objectives: We investigated whether preoperative serum low-density lipoprotein cholesterol (LDL-C) is associated with prognosis and midkine (MK; encoded by MDK)-related molecular features in colorectal cancer (CRC). Methods: This exploratory translational study integrated a retrospective cohort of 437 surgically treated patients, CRC-focused public transcriptomic analyses of MDK, independent functional enrichment of STRING-derived MK interactors, and immunohistochemistry in tumors from the lowest and highest LDL-C quartiles (n = 10 per group). Overall survival was analyzed using Cox proportional hazards regression. Results: MDK mRNA expression was elevated in CRC and was associated with adverse clinicopathological features. STRING-derived MK interactors showed significant Gene Ontology enrichment for lipoprotein- and low-density lipoprotein-particle receptor-related functions. KEGG cholesterol metabolism showed nominal enrichment but did not remain significant after multiple-testing correction. In the clinical cohort, each 1 mmol/L increase in LDL-C was independently associated with a lower mortality risk (adjusted HR = 0.612, 95% CI, 0.361–0.998; p = 0.048). Tumors from the lowest LDL-C quartile showed higher MK and c-Fos expression and lower ABCA1 expression than tumors from the highest quartile. Conclusions: Lower preoperative LDL-C was associated with poorer overall survival and with exploratory tissue-level molecular differences in CRC. These independent data layers support an associative, hypothesis-generating framework that requires prospective and mechanistic validation.