Ficd, also known as filamentation induced by cyclic-AMP domain protein or HYPE, is a bifunctional enzyme. It plays a crucial role in regulating the function of the endoplasmic reticulum (ER)-resident HSP70 chaperone, binding immunoglobulin protein (BiP), through AMPylation and deAMPylation. This regulation is part of the unfolded protein response (UPR) pathway, which is vital for maintaining protein folding homeostasis in the ER and proper cellular function [1,2,3,4,5,6].

In mouse models, FicD deficiency has shown diverse impacts. In mouse embryonic fibroblasts, deletion of FicD leads to widespread gene expression changes, dampened UPR signaling, altered cell stress recovery response, and unconstrained protein secretion, indicating its importance in tampering UPR signaling, stress recovery, and secretory protein homeostasis [1,4]. In the heart, FICD deficiency prevents pressure overload-associated heart failure, hypertrophy, and fibrosis by enhancing BiP-dependent UPR ER induction and ER-phagy [2]. In the murine liver, livers lacking FicD exhibit enhanced UPR signaling in response to short-term physiologic fasting and feeding stress, but remain resilient to chronic high-fat diet feeding or acute pathological UPR induction. However, repeated pathological UPR induction leads to changes in UPR induction and weight loss patterns in FicD-/-mice, suggesting FicD's role in regulating UPR responses during mild physiological stress and adaptation to repeated stresses [3,5].

In conclusion, Ficd is essential for regulating the UPR pathway and maintaining protein folding homeostasis in the ER. The FicD KO/CKO mouse models have revealed its significance in various disease-related processes such as heart failure, metabolic stress responses in the liver, and stress recovery in fibroblasts. Understanding Ficd's function through these models provides insights into potential therapeutic strategies for related diseases.