Phytanoyl-CoA hydroxylase-interacting protein-like (PHYHIPL) gene expression is altered in conditions like global ischemia, glioblastoma multiforme (GBM), and intrahepatic cholangiocarcinoma (iCCA) [1,2,3]. Its role in cell metabolism has been hypothesized based on protein-protein interactions (PPI) net analysis, and it may be involved in pathways such as TNF signaling, IL-17 signaling, retrograde endocannabinoid signaling, and cAMP signaling, as indicated by bioinformatics analysis in relation to GBM [2].

PHYHIPL Ser19Stop knock-in mice were generated to study the gene's function. The results showed that PHYHIPL impacts the morphology of cerebellar Purkinje cells (PCs), the innervation of climbing fibers to PCs, the inhibitory inputs to PCs from molecular layer interneurons, and motor learning ability, suggesting that the Ser19Stop SNP of the PHYHIPL gene may be associated with cerebellum-related diseases [1]. In addition, down-regulation of PHYHIPL in GBM is accompanied by poor overall survival, indicating it is a protection gene in GBM development, and its down-regulation mechanism may be related to mutations of the ß-catenin gene and endogenous siRNA [2]. In iCCA, decrease of PHYHIPL was correlated with better survival, and Rho GTPases-formins signalling was activated in PHYHIPL down-regulated tumours [3].

In conclusion, model-based research, especially the PHYHIPL Ser19Stop knock-in mouse model, has revealed that PHYHIPL plays a role in cerebellar development and function, and is associated with diseases like GBM and iCCA. Understanding the function of PHYHIPL through these models helps in uncovering the mechanisms underlying these diseases, potentially providing new insights for diagnosis, treatment, and prognosis.