Retinol Saturase (RetSat) is an oxidoreductase. It was initially described to transform retinol to 13,14-dihydroretinol. It is expressed in metabolically active tissues and is involved in multiple biological processes, such as adipocyte differentiation, hepatic glucose and lipid metabolism, macrophage function, vision, and the generation of reactive oxygen species (ROS) [4]. It also plays roles in pathways related to lipid metabolism, energy homeostasis, and cellular response to stress. Genetic models, like KO/CKO mouse models, have been crucial in understanding its functions.

In pluripotent stem cells, RetSat deletion led to chromosome instability, with phenomena like chromosome bridging, lagging, and interphase micronuclei. RetSat-knockout mouse embryonic stem cells upregulated cancer-associated gene pathways and showed higher tumorigenic capacities in teratoma formation assay. Mechanistically, RetSat interacts with cohesin/condensin components, and its deletion impaired the chromosome loading dosage of related proteins, highlighting its role in chromosome condensation in pluripotent stem cells [3].

In pancreatic ductal adenocarcinoma, high RetSat expression correlated with poor survival and resistance to gemcitabine-based chemotherapy. RetSat promoted fork restarting under replication stress and interacted with DDX39B to resolve R-loops, maintaining genomic stability [1].

In the context of ferroptosis in cancer cells, RetSat depletion protected cells from lipid peroxidation and ferroptosis-induced cell death, as it promotes ferroptosis by transforming retinol to 13,14-dihydroretinol [2].

In adipose tissue, cold exposure induced RetSat expression via β -adrenergic signaling. BAT-specific deletion of RetSat in mice impaired acute cold tolerance and lipolysis in adipocytes [6].

In the intestine, intestine-specific RetSat deletion in adult mice reduced weight gain and fat mass in HFD-fed mice and improved epithelial architecture in colitis [5].

In summary, RetSat is essential in multiple biological processes. Model-based research, especially KO/CKO mouse models, has revealed its significance in various disease areas. It plays key roles in maintaining chromosome stability in pluripotent stem cells, influencing cancer cell behavior in pancreatic ductal adenocarcinoma and cancer cell susceptibility to ferroptosis, as well as regulating lipid metabolism and cold tolerance in adipose tissue and weight gain and epithelial homeostasis in the intestine.