Abstract
<title>Abstract</title> <p>We integrated DepMap CRISPR dependency profiles with PRISM viability responses to estimate five-fold cross-fitted, covariate-adjusted associations with selective sensitivity to lipophilic versus hydrophilic statins. UBIAD1 and MVK showed strong associations, while SLC45A4 exhibited a smaller, positive association that remained stable across cross-fitting seeds. These findings showed directional consistency across CTRP and PRISM secondary AUC outcomes. Using secondary dose–response data, the association with SLC45A4 was particularly pronounced in colorectal cell lines for both AUC and the fitted lower asymptote, whereas the corresponding colorectal interaction was near zero for the primary phenotype. Colorectal co-dependency and CCLE metabolomics showed patterns consistent with sterol- and polyamine-related pathways. Compared with 1,000 random genes, SLC45A4 lay in the empirical tail for raw coefficients. However, this pattern was less pronounced under a standardized z-score comparison that accounts for differing GeneEffect variance across genes. Specifically, the comparison was marginally significant for the primary outcome and farther into the tail for the secondary AUC. These analyses support SLC45A4 as a promising candidate for focused follow-up, including direct perturbation and pharmacological validation in colorectal cell lines.</p>