FNDC5, also known as fibronectin type III domain-containing protein 5, is a transmembrane protein expressed in skeletal muscle, heart, and brain [3]. It is the precursor of the myokine irisin, which is released upon cleavage of FNDC5. FNDC5 is involved in multiple biological processes. It is linked to the PGC-1α pathway, and together they regulate the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, which is important for cognitive function [2]. It also plays a role in maintaining metabolic homeostasis, and its dysregulation can lead to systemic metabolism imbalance and metabolic disorders [6]. Gene knockout mouse models are valuable for studying FNDC5's function.

In AD models, knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice, while boosting its levels rescues synaptic plasticity and memory. Blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice, indicating it is an important mediator of exercise-induced benefits in AD [1]. In doxorubicin-induced cardiotoxicity, Fndc5 deficiency in H9C2 cells increases oxidative damage and apoptosis, mimicking the in-vivo phenotype, while FNDC5 overexpression or irisin treatment alleviates these effects [4]. In intervertebral disc degeneration, knocking out FNDC5 compromises the beneficial effects of physical exercise, and overexpression of FNDC5 in NP tissue alleviates disc degeneration [5].

In conclusion, FNDC5 plays essential roles in cognitive function, metabolism, and protection against various diseases. Studies using FNDC5 knockout mouse models have revealed its significance in Alzheimer's disease, doxorubicin-induced cardiotoxicity, and intervertebral disc degeneration. These findings highlight its potential as a therapeutic target for these conditions.