OPLAH, encoding for 5-oxoprolinase, is a member of the γ -glutamyl cycle. It functions by scavenging 5-oxoproline, an important mediator of oxidative stress [1,3]. The γ -glutamyl cycle is related to glutathione metabolism, and OPLAH's role in this cycle is crucial for maintaining cellular redox balance and normal physiological function [4].

In Oplah full-body knock-out (KO) mice, higher 5-oxoproline levels led to increased oxidative stress, cardiac and renal fibrosis, elevated left ventricular filling pressures, and impaired left ventricular relaxation, presenting a heart failure with a preserved ejection fraction (HFpEF)-like phenotype [1]. In Chinese hamsters with type 2 diabetes mellitus, downregulation of OPLAH in skeletal muscles affected insulin resistance and glucose uptake, as knockdown of OPLAH in human skeletal muscle cells increased reactive oxygen species content and inhibited the PI3K/Akt/GLUT4 signaling pathway [2].

In conclusion, OPLAH plays a vital role in maintaining redox balance through its function in the γ -glutamyl cycle. Gene knockout models, such as the KO mice, have revealed its significance in diseases like HFpEF and type 2 diabetes, providing insights into the underlying mechanisms and potential therapeutic targets for these conditions.