FKBP5, also known as FKBP51, is a gene encoding a co-chaperone protein. It is involved in the modulation of glucocorticoid receptor interaction, playing a key role in the adaptive stress response pathway. The intracellular concentration of FKBP5 affects the binding affinity of the glucocorticoid receptor to glucocorticoids [3]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying FKBP5 function.

In a cardiomyocyte-specific FKBP5 knockdown (a form of loss-of-function) mouse model, downregulation of FKBP5 promoted atrial arrhythmogenesis. This was associated with action potential alternans, spontaneous Ca2+ waves, and increased NCX1 levels. FKBP5-deficiency enhanced Slc8a1 (encoding NCX1) transcription via hypoxia-inducible factor 1α, and FKBP5 negatively modulated hypoxia-inducible factor 1α protein levels by interacting with heat-shock protein 90 [1]. In Fkbp5ko mice related to multiple sclerosis study, the progress of myelin loss and regeneration was slower compared to wild-type mice, with mitophagy playing a regulatory role. FKBP5 was found to activate mitophagy by ablating PPAR-γ [2]. In aged Fkbp5 KO mice, there were no significant changes in circadian rhythms, but protection against stress-mediated disruptions in rhythmicity in a sex-dependent manner was observed. Also, protein changes in brain regions and sex-dependent alterations were detected, with elevated levels of proteins associated with neuronal-cell adhesion and synaptic integrity [4].

In conclusion, FKBP5 is crucial for processes like stress response, cardiac function, and myelin regulation. The KO/CKO mouse models have revealed its role in atrial arrhythmogenesis, multiple sclerosis-related myelin processes, and age-related brain changes. These findings provide insights into potential molecular mechanisms underlying certain diseases, highlighting the importance of FKBP5 in disease-related biological functions.