Molecular Mechanisms and Therapeutic Potential of DJ ‐1 in Skeletal Muscle Homeostasis and Disease

ABSTRACT The DJ‐1 protein was initially identified as an oncogene, but subsequent studies revealed its crucial protective role in neurodegenerative diseases. Increasing evidence indicates that DJ‐1 possesses critical physiological functions in skeletal muscle, but the underlying mechanisms remain to be systematically elucidated. Existing research has conclusively demonstrated that DJ‐1 is widely expressed in skeletal muscle and functions as a central hub integrating multiple pathways to establish a multi‐level cellular protection network: it safeguards energy metabolism by maintaining mitochondrial structure and function; enhances antioxidant capacity by directly scavenging ROS and regulating Nrf2/ARE signaling; and delays muscle aging by inhibiting protein aggregation and preserving protein homeostasis. Under pathological conditions, DJ‐1 dysfunction is closely associated with muscular dystrophy, inflammatory myopathy, metabolic myopathy, and muscle atrophy. Its abnormalities lead to mitochondrial damage, exacerbated oxidative stress, and disrupted protein homeostasis, ultimately triggering muscle structural deterioration. Based on these insights, researchers have developed various DJ‐1 regulatory strategies, including small‐molecule activators, transcriptional modulators, and functional peptide compounds, which show promising therapeutic potential. This review represents the first systematic, cross‐disease integration of DJ‐1's role in aging‐related sarcopenia, diabetic myopathy, inflammatory myopathies, and neuromuscular degenerative diseases. It elucidates DJ‐1's core function as a central integrator coordinating antioxidant defense, mitochondrial homeostasis, metabolic regulation, and protein homeostasis. A deeper understanding of DJ‐1's mechanisms will provide critical theoretical foundations for elucidating the common pathological basis of skeletal muscle diseases and developing novel therapeutic strategies.