Stearoyl-CoA desaturase 5 (SCD5) in lipid remodeling: From molecular control to pathophysiology

Stearoyl-CoA desaturase (SCD) forms double bonds at the Δ9 position of saturated acyl-CoAs, primarily palmitoyl-CoA, and stearoyl-CoA. Of the two human isoforms, SCD1 is ubiquitous, while the tissue-specific SCD5 is expressed in the brain, pancreas, and reproductive tissues, where it facilitates local lipid remodeling and modulates cellular signaling in a context-dependent manner. Its activity significantly impacts membrane composition, vesicular trafficking, and post-translational processing of Wnt proteins, thereby influencing cell fate and signal transduction pathways like EGFR and Akt. The multifaceted regulation of SCD5 involves transcriptional activation by SREBP1 and EGR2, as well as repression by HIF2α and NME2. Post-transcriptional modulation includes alternative splicing, which yields SCD5A and SCD5B variants, and the inhibitory actions of specific microRNAs, such as miR-221/222 and miR-145-5p. Notably, the SCD5 protein lacks the N-terminal PEST degradation motifs characteristic of SCD1, which contributes to its distinct stability profile across different cell types. SCD5 plays context-dependent roles in various human cancers. While its downregulation in melanoma and breast cancer is associated with advanced malignancy and epithelial-to-mesenchymal transition (EMT), its expression in glioblastoma stem-like cells is essential for survival and DNA repair. Beyond cancer, genetic polymorphisms and expression alterations of SCD5 have been linked to neurodegenerative diseases, psychiatric conditions like schizophrenia, and metabolic dysfunctions such as visceral adiposity and type 2 diabetes. Understanding these tissue-specific regulatory milieus is crucial for developing SCD5-targeted therapeutic strategies. Here, we review available knowledge regarding the structure, regulation, and function of SCD5, with focus on its role in cell signaling and disease.